Immunomodulatory peptides

ABSTRACT

A purified preparation of a peptide consisting essentially of an amino acid sequence identical to that of a segment of a naturally-occurring human protein, said segment being of 10 to 30 residues in length, inclusive, wherein said peptide binds to a human major histocompatibility complex (MHC) class II allotype.

The invention was made in the course of research funded in part by theU.S. Government under NIH Grant 5R35-CA47554; the U.S. Governmenttherefore has certain rights in the invention.

This application is a divisional of application Ser. No. 08/077,255,filed Jun. 15, 1993, which is a continuation-in-part of U.S. Ser. No.07/925,460, filed Aug. 11, 1992, now abandoned.

The field of the invention is major histocompatibility complex (MHC)antigens.

BACKGROUND OF THE INVENTION

Major histocompatibility complex (MHC) class II antigens are cellsurface receptors that orchestrate all specific immune responses invertebrates. Humans possess three distinct MHC class II isotypes: DR,for which approximately 70 different allotypes are known; DQ, for which33 different allotypes are known; and DP, for which 47 differentallotypes are known. Each individual bears two to four DR alleles, twoDQ alleles, and two DP alleles.

MHC receptors (both class I and class II) participate in the obligatefirst step of immune recognition by binding small protein fragments(peptides) derived from pathogens or other non-host sources, andpresenting these peptides to the regulatory cells (T cells) of theimmune system. In the absence of MHC presentation, T cells are incapableof recognizing pathogenic material. Cells that express MHC class IIreceptors are termed antigen presenting cells (APC). APCs ingestpathogenic organisms and other foreign materials by enveloping them inendosomic vesicles, then subjecting them to enzymatic and chemicaldegradation. Foreign proteins which are ingested by APCs are partiallydegraded or "processed" to yield a mixture of peptides, some of whichare bound by MHC class II molecules that are en route to the surface.Once on the cell surface, MHC-bound peptides are available for T cellrecognition.

MHC class II antigens are expressed on the surface of APCs as atrimolecular complex composed of an α chain, a β chain, and a processedpeptide. Like most polypeptides that are expressed on the cell surface,both α and β chains contain short signal sequences at their NH₂ terminiwhich target them to the endoplasmic reticulum (ER). Within the ER theclass II α/β chain complex associates with an additional protein termedthe invariant chain (Ii). Association with Ii is proposed to block thepremature acquisition of peptides (by blocking the peptide binding cleftof the MHC heterodimer), promote stable α/β interaction, and directsubsequent intracellular trafficking of the complex to endosomalvesicles. In the endosomes, Ii is removed by a process involvingproteolysis; this exposes the peptide binding cleft, thus allowingpeptides present in the endosome to bind to the MHC molecule. The classII/peptide complex is transported from the endosomes to the cell surfacewhere it becomes accessible to T-cell recognition and subsequentactivation of immune responses. Class II MHC molecules bind not only topeptides derived from exogenous (ingested) proteins, but also to thoseproduced by degradation of endogenous (self) proteins. The amount ofeach species of peptide which binds class II is determined by its localconcentration and its relative binding affinity for the given class IIbinding groove, with the various allotypes displaying differentpeptide-binding specificities.

Early during fetal development, the mammalian immune system is"tolerized", or taught not to react, to self-peptides. The stability andmaintenance of this system is critical for ensuring that an animal doesnot generate an immune response against self. A breakdown of this systemgives rise to autoimmune conditions such as diabetes, rheumatoidarthritis and multiple sclerosis. Current technologies intended tomanipulate the immune system into reestablishing propernonresponsiveness include protocols involving the intravenous deliveryof synthetic, high affinity binding peptides as blocking peptides.

Vaccination can generate protective immunity against a pathogenicorganism by stimulating an antibody-mediated and/or a T cell-mediatedresponse. Most of the current vaccination strategies still userelatively crude preparations, such as attenuated or inactivatedviruses. These vaccines often generate both antibody- and cell-mediatedimmunity, and do not allow one to modulate the type of immune responsegenerated. Moreover, in many diseases the generation of the wrong typeof response can result in an exacerbated disease state.

SUMMARY OF THE INVENTION

In the work disclosed herein, naturally processed peptides bound to sixof the some 70 known human MHC class II DR allotypes (HLA-DR1, HLA-DR2,HLA-DR3, HLA-DR4, HLA-DR7, and HLA-DR8) have been characterized. Thesepeptides were found to be predominantly derived from self proteinsrather than foreign proteins. Several self peptide families have beenidentified with the unexpected property of degenerate binding: that is,a given self-peptide will bind to a number of HLA-DR allotypes. Thisobservation runs counter to the widely-accepted view of MHC class IIfunction, which dictates that each allotype binds a different set ofpeptides. Furthermore, many if not all of the self-peptides disclosedherein bind to the class II molecules with relatively high affinity.These three characteristics--(1) self rather than foreign, (2)degeneracy, and (3) high affinity binding--suggest a novel means fortherapeutic intervention in disease conditions characterized byautoreactivity, such as Type I diabetes, rheumatoid arthritis, andmultiple sclerosis. In addition, such therapy could be used to reducetransplant rejection.

In the therapeutic methods of the invention, short peptides modelled onthe high-affinity immunomodulating self peptides of the invention (whichpreferably are nonallelically restricted) are introduced into the APCsof a patient. Tissue typing to determine the particular class II allelesexpressed by the patient may be unnecessary, as the peptides of theinvention are bound by multiple class II isotypes. It may be useful toemploy a "cocktail" of peptides, where complete degeneracy is lackingfor individual peptides, i.e., where peptides binds to fewer than allallotypes; the cocktail provides overlapping binding specificity. Oncein the APC, a peptide binds to the class II molecules with highaffinity, thereby blocking the binding of immunogenic peptides which areresponsible for the immune reaction characteristic of the diseasecondition. Because the blocking peptides of the invention are selfpeptides with the exact carboxy and amino termini tolerized duringontogeny, they are immunologically inert and will not induce an immuneresponse which may complicate treatment using non-self blockingpeptides.

The peptides of the invention may be introduced into APCs directly,e.g., by intravenous injection of a solution containing one or more ofthe peptides. Alternatively, the APCs may be provided with a means ofsynthesizing large quantities of the blocking peptides intracellularly.Recombinant genes that encode ER and/or endosomal targeting signalsfused to blocking peptide sequences are linked to appropriate expressioncontrol sequences and introduced into APCs. Once in the cell, thesegenes direct the expression of the hybrid peptides. Peptides targeted tothe ER will bind class II α and β chains as they are translated andassembled into heterodimers. The presence of high affinity bindingpeptides within the ER will prevent association of the α/β complex withinvariant chain, and thus interfere with intracellular trafficking. Theclass II molecule/blocking peptide complex may subsequently be expressedon the cell surface, but would not elicit an immune response since Tcells are tolerized to this complex early in development. The use ofpeptides tagged with ER retention signals may also prevent thepeptide-complexed class II molecules from leaving the ER. Alternatively,the recombinant peptide may be tagged with an endosomal targeting signalwhich directs it to the endosomal compartment after synthesis, therebyalso skewing the ratio of endogenously-processed peptide to blockingpeptide in the endosome and favoring binding of the high affinityblocking peptide to any class II molecules which did not bind it in theER. It may be advantageous, for any individual patient, to employ one ormore ER-directed peptides in combination with one or moreendosome-directed peptide, so that α-β complexes which are not filled inthe ER with peptides of the invention are then blocked in the endocyticpathway. The end result again is cell surface expression of anon-immunogenic class II/peptide complex.

The use of a class II nonrestricted high affinity binding peptidecoupled to an intracellular delivery system permits the specificdown-regulation of class II restricted immune responses without invokingthe pleiotropic adverse reactions associated with the currentpharmacological strategies. Successful application of these technologieswill constitute a significant advance towards the treatment ofautoimmune disease and prevention of transplant rejection.

The intracellular delivery system of the invention can also be utilizedin a novel method of vaccination of an animal, e.g., a human patient ora commercially significant mammal such as a cow which is susceptible todiseases such as hoof and mouth disease. Such a system can be tailoredto generate the type of immune response required in a given situation byadjustments in the following: (a) peptide specificity for class I orclass II MHC; (b) peptide/protein length and/or sequence, and (c) usingspecific tags for organelle targeting. The system of the inventionensures that peptides are produced only within cells, and are notpresent outside the cells where they could stimulate antibody productionby contact with B cells. This limits the immune response generated bysuch a vaccine to T cell-mediated immunity, thereby preventing either aninappropriate or potentially deleterious response as might be observedwith standard vaccines targeting the organisms which cause, for example,HIV, malaria, leprosy, and leishmaniasis. Furthermore, this exclusivelyT cell-mediated immune response can be class I or class II-based, orboth, depending upon the length and character of the immunogenicpeptides: MHC class I molecules are known to bind preferentially topeptides 8 to 10 residues in length, while class II molecules bind withhigh affinity to peptides that range from 12 to 25 residues long.

Immunization and therapy according to the invention can employ apurified preparation of a peptide of the invention, i.e., a peptidewhich includes an amino acid sequence identical to that of a segment ofa naturally-occurring human protein (i.e., a "self protein"), suchsegment being of 10 to 30 residues in length, wherein the peptide bindsto a human MHC class II allotype, and preferably binds to at least twodistinct MHC class II allotypes (e.g., any of the approximately 70 knownDR allotypes, approximately 47 known DP allotypes, or approximately 33known DQ allotypes). The portion of the peptide corresponding to theself protein segment is herein termed a "self peptide". By "purifiedpreparation" is meant a preparation at least 50% (by weight) of thepolypeptide constituents of which consists of the peptide of theinvention. In preferred embodiments, the peptide of the inventionconstitutes at least 60% (more preferably at least 80%) of the purifiedpreparation. The naturally-occurring human protein is preferably HLA-A2(as broadly defined below), HLA-A29, HLA-A30, HLA-B44, HLA-B51,HLA-Bw62, HLA-C, HLA-DP β-chain, HLA-DQ α-chain, HLA-DQ β-chain,HLA-DQ3.2 β-chain, HLA-DR α-chain, HLA-DR β-chain, HLA-DR4 β-chain,invariant chain (Ii), Ig kappa chain, Ig kappa chain C region, Ig heavychain, Na⁺ /K⁺ ATPase, potassium channel protein, sodium channelprotein, calcium release channel protein, complement C9,glucose-transport protein, CD35, CD45, CD75, vinculin, calgranulin B,kinase C ζ-chain, integrin β-4 gp150, hemoglobin, tubulin α-1 chain,myosin β-heavy chain, α-enolase, transferrin, transferrin receptor,fibronectin receptor α-chain, acetylcholine receptor, interleukin-8receptor, interferon α-receptor, interferon γ-receptor, calcitoninreceptor, LAM (lymphocyte activation marker) Blast-1, LAR (leukocyteantigen-related) protein, LIF (leukemia inhibitory factor) receptor, 4F2cell-surface antigen (a cell-surface antigen involved in normal andneoplastic growth) heavy chain, cystatin SN, VLA-4 (a cell surfaceheterodimer in the integrin superfamily of adhesion receptors), PAI-1(plasminogen activator inhibitor-1), IP-30 (interferon-γ inducedprotein), ICAM-2, carboxypeptidase E, thromboxane-A synthase,NADH-cytochrome-b5 reductase, c-myc transforming protein, K-rastransforming protein, MET kinase-related transforming protein,interferon-induced guanylate-binding protein, mannose-binding protein,apolipoprotein B-100, cathepsin C, cathepsin E, cathepsin S, FactorVIII, von Willebrand factor, metalloproteinase inhibitor 1 precursor,metalloproteinase inhibitor 2, plasminogen activator inhibitor-1, orheat shock cognate 71 kD protein; it may be an MHC class I or II antigenprotein or any other human protein which occurs at the cell surface ofAPCs. The self peptide preferably conforms to the following motif: at afirst reference position (I) at or within 12 residues of the aminoterminal residue of the segment, a positively charged residue (i.e.,Lys, Arg, or His) or a large hydrophobic residue (i.e., Phe, Trp, Leu,Ile, Met, Tyr, or Pro; and at position I+5, a hydrogen bond donorresidue (i.e., Tyr, Asn, Gln, Cys, Asp, Glu, Arg, Ser, Trp, or Thr). Inaddition, the peptide may also be characterized as having, at positionsI+9, I+1, and/or I-1, a hydrophobic residue (i.e., Phe, Trp, Leu, Ile,Met, Pro, Ala, Val, or Tyr) (+denotes positions to the right, or towardthe carboxy terminus, and--denotes positions to the left, or toward theamino terminus.) A typical peptide of the invention will include asequence corresponding to residues 32-41 (i.e., TQFVRFDSDA; SEQ ID NO:149) or residues 107-116 (i.e., DWRFLRGYHQ; SEQ ID NO: 150) of HLA-A2,or residues 108-117 (i.e., RMATPLLMQA; SEQ ID NO: 151) of Ii, or asequence essentially identical to any one of the sequences set forth inTables 1-10 below.

The therapeutic and immunization methods of the invention can alsoemploy a nucleic acid molecule (RNA or DNA) encoding a peptide of theinvention, but encoding less than all of the entire sequence of the selfprotein. The nucleic acid preferably encodes no substantial portion ofthe self protein other than the specified self peptide which binds to aMHC class II molecule, although it may optionally include a signalpeptide or other trafficking sequence which was derived from the selfprotein (or from another protein). A trafficking sequence is an aminoacid sequence which functions to control intracellular trafficking(directed movement from organelle to organelle or to the cell surface)of a polypeptide to which it is attached. Such trafficking sequencesmight traffic the polypeptide to ER, a lysosome, or an endosome, andinclude signal peptides (the amino terminal sequences which directproteins into the ER during translation), ER retention peptides such asKDEL (SEQ ID NO: 152); and lysosome-targeting peptides such as KFERQ(SEQ ID NO: 153), QREFK (SEQ ID NO: 154), and other pentapeptides havingQ flanked on one side by four residues selected from K, R, D, E, F, I,V, and L. An example of a signal peptide that is useful in the inventionis a signal peptide substantially identical to that of an MHC subunitsuch as class II α or β; e.g., the signal peptide of MHC class II a iscontained in the sequence MAISGVPVLGFFIIAVLMSAQESWA (SEQ ID NO: 155).The signal peptide encoded by the nucleic acid of the invention mayinclude only a portion (e.g., at least ten amino acid residues) of thespecified 25 residue sequence, provided that portion is sufficient tocause trafficking of the polypeptide to the ER. In preferredembodiments, the nucleic acid of the invention encodes a second selfpeptide and a second trafficking sequence (which may be identical to ordifferent than the first self peptide and first trafficking sequence),and it may encode additional self peptides and trafficking sequences aswell. In still another variation on this aspect of the invention, theself peptide sequence (or a plurality of self peptide sequences arrangedin tandem) is linked by a peptide bond to a substantially intact Iipolypeptide, which then carries the self peptide sequence along as ittraffics the class II molecule from ER to endosome.

The nucleic acid of the invention may also contain expression controlsequences (defined as transcription and translation start signals,promoters, and enhancers which permit and/or optimize expression of thecoding sequence with which they are associated) and/or genomic nucleicacid of a phage or a virus, such as an attenuated or non-replicative,non-virulent form of vaccinia virus, adenovirus, Epstein-Barr virus, ora retrovirus.

The peptides and nucleic acids of the invention may be prepared fortherapeutic use by suspending them directly in a pharmaceuticallyacceptable carrier, or by encapsulating them in liposomes,immune-stimulating complexes (ISCOMS), or the like. Such preparationsare useful for inhibiting an immune response in a human patient, bycontacting a plurality of the patient's APCs with the therapeuticpreparation and thereby introducing the peptide or nucleic acid into theAPCs.

Also within the invention is a cell (e.g., a tissue culture cell or acell, such as a B cell or APC, within a human) containing the nucleicacid molecule of the invention. A cultured cell containing the nucleicacid of the invention may be used to manufacture the peptide of theinvention, in a method which involves culturing the cell underconditions permitting expression of the peptide from the nucleic acidmolecule.

Disclosed herein is a method of identifying a nonallelically restrictedimmunomodulating peptide, which ethod includes the steps of:

(a) fractionating a mixture of peptides eluted from a first MHC class IIallotype;

(b) identifying a self peptide from this mixture; and

(c) testing whether the self peptide binds to a second MHC class IIallotype, such binding being an indication that the self peptide is anonallelically restricted immunomodulating peptide.

In further embodiments, the invention includes a method of identifying apotential immunomodulating peptide, in a method including the steps of:

(a) providing a cell expressing MHC class II molecules on its surface;

(b) introducing into the cell a nucleic acid encoding a candidatepeptide; and

(c) determining whether the proportion of class II molecules which arebound to the candidate peptide is increased in the presence of thenucleic acid compared to the proportion bound in the absence of thenucleic acid, such an increase being an indication that the candidatepeptide is a potential immunomodulating peptide.

Also within the invention is a method of identifying a potentialimmunomodulating peptide, which method includes the steps of:

(a) providing a cell expressing MHC class II molecules on its surface;

(b) introducing into the cell a nucleic acid encoding a candidatepeptide; and

(c) determining whether the level of MHC class II molecules on thesurface of the cell is decreased in the presence of the nucleic acidcompared to the level of MHC class II molecules in the absence of thenucleic acid, such a decrease being an indication that the candidatepeptide is a potential immunomodulating peptide.

Also included in the invention is a method of identifying anonallelically restricted immunostimulating peptide, which methodincludes the steps of:

(a) providing a cell bearing a first MHC class I or class II allotype,such cell being infected with a pathogen (e.g., an infective agent whichcauses human or animal disease, such as human immunodeficiency virus(HIV), hepatitis B virus, measles virus, rubella virus, influenza virus,rabies virus, Corynebacterium diphtheriae, Bordetella pertussis,Plasmodium spp., Schistosoma spp., Leishmania spp., Trypanasoma spp., orMycobacterium lepre);

(b) eluting a mixture of peptides bound to the cell's first MHCallotype;

(c) identifying a candidate peptide from the mixture, such candidatepeptide being a fragment of a protein from the pathogen; and

(d) testing whether the candidate peptide binds to a second MHCallotype, such binding being an indication that the candidate peptide isa nonallelically restricted immunostimulating peptide. A nucleic acidencoding such an immunogenic fragment of a protein of a pathogen can beused in a method of inducing an immune response in a human patient,which method involves introducing the nucleic acid into an APC of thepatient.

The therapeutic methods of the invention solve certain problemsassociated with prior art methods involving intravenous injection ofsynthetic peptides: (1) because of allelic specificity, a peptidecapable of binding with high affinity to all, or even most, of thedifferent class II allotypes expressed within the general population hadnot previously been identified; (2) the half-lives of peptides deliveredintravenously are generally very low, necessitating repeatedadministration with the associated high level of inconvenience and cost;(3) this type of delivery approach requires that the blocking peptidedisplace the naturally-occurring peptide occupying the binding cleft ofa class II molecule while the latter is on the cell surface, which isnow believed to be a very inefficient process; and (4) if the blockingpeptide utilized is itself immunogenic, it may promote deleteriousimmune responses in some patients.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DETAILED DESCRIPTION

The drawings are first briefly described.

Drawings

FIGS. 1A-1F are chromatographic analyses of the peptide pools extractedfrom papain digested HLA-DR1, DR2, DR3, DR4, DR7, and DR8, respectively,illustrating the peptide repertoire of each HLA-DR as detected by UVabsorbance. The UV absorbance for both 210 nm and 277 nm is shown at afull scale absorbance of 500 mAU with a retention window between 16minutes and 90 minutes (each mark represents 2 minutes).

FIG. 2 is a representative mass spectrometric analysis of the sizedistribution of isolated HLA-DR1 bound peptides. The determined peptidemasses in groups of 100 mass units were plotted against the number ofisolated peptides identified by mass spectrometry. Peptide length wascalculated by dividing the experimental mass by an average amino acidmass of 118 daltons.

FIG. 3A is a representation of a minigene of the invention (SEQ ID NO:147), in which the HLA-DRα chain leader peptide is linked to the aminoterminus of a 15-residue blocking peptide fragment of human invariantchain Ii.

FIG. 3B is a representation of a second minigene of the invention (SEQID NO: 148), in which the HLA-DRα chain leader peptide is linked to theamino terminus of a 24-residue blocking peptide fragment of humaninvariant chain Ii.

EXPERIMENTAL DATA METHODS

I. Purification of HLA-DR antigens.

HLA-DR molecules were purified from homozygous, Epstein-Barrvirus-transformed, human B lymphoblastoid lines: DR1 from LG-2 cells,DR2 from MST cells, DR3 from WT20 cells, DR4 from Priess cells, DR7 fromMann cells, and DR8 from 23.1 cells. All of these cell lines arepublicly available. Cell growth, harvest conditions and proteinpurification were as previously described (Gorga, J. et al., 1991).Briefly, 200 grams of each cell type was resuspended in 10 mM Tris-HCl,1 mM dithiothreitol (DTT), 0.1 mM phenylmethylsulfonylflouride (PMSF),pH 8.0, and lysed in a Thomas homogenizer. The nuclei were removed bycentrifugation at 4000×g for 5 min and the pellets washed and repelleteduntil the supernatants were clear. All the supernatants were pooled andthe membrane fraction harvested by centrifugation at 175,000×g for 40min. The pellets were then resuspended in 10 mM Tris-HCl, 1 mM DTT, 1 mMPMSF, 4% NP-40. The unsolubilized membrane material was removed bycentrifugation at 175,000×g for 2 hours, and the NP-40 solublesupernatant fraction used in immunoaffinity purification.

Detergent soluble HLA-DR was bound to a LB3.1-protein A SEPHAROSE™agarose gel column (Pharmacia; (Gorga et al., id) and eluted with 100 mMglycine, pH 11.5. Following elution, the sample was immediatelyneutralized by the addition of Tris-HCl and then dialyzed against 10 mMTris-HCl, 0.1% deoxycholic acid (DOC). The LB3.1 monoclonal antibodyrecognizes a conformational determinant present on the nonpolymorphicHLA-DRα chain, and thus recognizes all allotypes of HLA-DR.

The transmembrane domain of the DR molecules was removed by papaindigestion, and the resulting water-soluble molecule further purified bygel filtration chromatography on an S-200 column equilibrated in 10 mMTris-HCl, pH 8.0. The purified DR samples were concentrated byultrafiltration, yield determined by BCA assay, and analyzed by SDSpolyacrylamide gel electrophoresis.

II. Extraction and fractionation of bound peptides.

Water-soluble, immunoaffinity-purified class II molecules were furtherpurified by high-performance size exclusion chromatography (SEC), in 25mM N-morpholino ethane sulfonic acid (MES) pH 6.5 and a flowrate of 1ml/min., to remove any residual small molecular weight contaminants.Next, CENTRICON™ ultrafiltration microconcentrators (molecular weightcutoff 10,000 daltons) (Amicon Corp.) were sequentially washed using SECbuffer and 10% acetic acid prior to spin-concentration of the proteinsample (final volume between 100-200 μl). Peptide pools were extractedfrom chosen class II alleles by the addition of 1 ml of 10% acetic acidfor 15 minutes at 70° C. These conditions are sufficient to free boundpeptide from class II molecules, yet mild enough to avoid peptidedegradation. The peptide pool was separated from the class II moleculeafter centrifugation through the CENTRICON™ ultrafiltrationmicroconcentrator, with the flow-through containing the previously boundpeptides.

The collect ed acid-extracted peptide pool was concentrated in aSPEED-VAC™ vacuum equipped centrifuge (Savant) to a volume of 50 μlprior to HPLC separation. Peptides were separated on a microbore C-18reversed-phase chromatography (RPC) column (Vydac) utilizing thefollowing non-linear gradient protocol at a constant flowrate of 0.15ml/min.: 0-63 min. 5%-33% buffer B; 63-95 min. 33%-60% buffer B; 95-105min 60%-80% buffer B, where buffer A was 0.06% trifluoroaceticacid/water and buffer B was 0.055% trifluoroacetic acid/acetonitrile.Chromatographic analysis was monitored at multiple UV wavelengths (210,254, 277, and 292 nm) simultaneously, permitting spectrophotometricevaluation prior to mass and sequence analyses. Shown in FIG. 1 arechromatograms for each of the six DR peptide pools analyzed. Collectedfractions were subsequently analyzed by mass spectrometry and Edmansequencing.

III. Analysis of peptides.

The spectrophotometric evaluation of the peptides during RPC providesvaluable information regarding amino acid composition (contribution ofaromatic amino acids) and is used as a screening method for subsequentcharacterization. Appropriate fractions collected during the RPCseparation were next analyzed using a Finnegan-MAT LASERMAT™matrix-assisted laser-desorption mass spectrometer (MALD-MS) todetermine the individual mass values for the predominant peptides.Between 1%-4% of the collected fraction was mixed with matrix (1 μlα-Cyano-4-hydroxycinnamic acid) to achieve mass determination ofextracted peptides. The result of this analysis for HLA-DR1 is shown inFIG. 2. Next, chosen peptide samples were sequenced by automated Edmandegradation microsequencing using an ABI 477A protein sequencer (AppliedBiosystems) with carboxy-terminal verification provided by mass spectralanalysis using the Finnigan-MAT TSQ 700 triple quadruple massspectrometer equipped with an electro-spray ion source. This parallelanalysis ensures complete identity of peptide composition and sequence.Peptide alignment with protein sequences stored in the SWISS-PROTdatabase was performed using the FASTA computer database search program.Set forth in Tables 1-10 are the results of this sequence analysis foreach of the DR molecules studied.

RESULTS

I. HLA-DR1.

The HLA-DR1 used in this study was papain solubilized to enable thematerial to be used both for crystallographic and bound peptideanalyses. The peptides bound to DR1 were acid extracted and fractionatedusing RPC (FIG. 1). The absence of any detectable peptidic materialfollowing a second extraction/RPC separation verified quantitativepeptide extraction. Amino acid analysis (ABI 420A/130A derivatizer/HPLC)of extracted peptide pools demonstrated a 70-80% yield, assuming totaloccupancy of purified DR1 with a molar equivalent of bound peptidescorresponding to the size distribution determined by mass spectrometry(see FIG. 2). The RPC profiles obtained from DR1 extractions of multipleindependent preparations were reproducible. Furthermore, profiles fromeither detergent-soluble or papain-solubilized DR1 were equivalent. Toconfirm that the peptides were in fact identical in detergent-solubleand papain-digested DR1, mass spectrometry and Edman sequencing analyseswere performed and revealed identical masses and sequences for analogousfractions from the two preparations.

Matrix-assisted laser desorption mass spectrometry (MALD-MS) was used toidentify 111 species of unique mass contained within the eluted peptidepool of DR1 with an average size of 18 and a mode of 15 residues (FIG.2). Over 500 additional mass species present within the molecular weightrange of 13-25 residues were detected; however, the signal was notsufficient to assign individual masses with confidence. Multiple speciesof varying mass were detected in fractions corresponding to single RPCpeaks indicating co-elution of peptides. To characterize these peptidesfurther, samples were analyzed in parallel on a triple quadruple massspectrometer equipped with an electrospray ion source (ESI-MS) and byautomated Edman degradation microsequencing (Lane et al., J. Prot. Chem.10:151-160 (1991)). Combining these two techniques permits crucialverification of both the N- and C-terminal amino acids of peptidescontained in single fractions. The sequence and mass data acquired fortwenty peptides isolated from DR1 are listed in Table 1. All theidentified peptides aligned with complete identity to regions ofproteins stored in the SWISS-PROT database.

Surprisingly, sixteen of the twenty sequenced DR1-bound peptides were100% identical to regions of the self proteins HLA-A2 and classII-associated invariant chain (Ii), representing at least 26% of thetotal extracted peptide mass. These isolated peptides varied in lengthand were truncated at both the N- and C-termini, suggesting that: 1)antigen processing occurs from both ends after binding to DR1, or 2)class II molecules bind antigen from a pool of randomly generatedpeptides. The yields from the peptide microsequencing indicated thatHLA-A2 (FIG. 1) and Ii each represents at least 13% of the totalDR1-bound peptides.

An additional surprising finding concerned a peptide which, althoughbound to HLA-DR and 100% homologous with HLA-A2 peptide, was derivedfrom a cell which does not express HLA-A2 protein. Evidently thispeptide is derived from a protein containing a region homologous with aregion of HLA-A2 protein. Thus, for purposes of this specification, theterm "HLA-A2 protein" is intended to include HLA-A2 protein itself, aswell as any naturally occurring protein which contains a ten or greateramino acid long region of >80% homology with an HLA-DR-binding peptidederived from HLA-A2. An "HLA-A2 peptide" similarly refers to peptidesfrom any HLA-A2 protein, as broadly defined herein.

The other four peptides identified in the DRI studies were derived fromtwo self proteins, transferrin receptor and the Na⁺ /K⁺ ATPase, and oneexogenous protein, bovine serum fetuin (a protein present in the serumused to fortify the medium which bathes the cells). Each of thesepeptides occupied only 0.3-0.6% of the total DRI population,significantly less than either the HLA-A2 or the Ii peptides. It isknown that class II molecules en route to the cell surface intersect thepathway of incoming endocytic vesicles. Both recycling membrane proteinsand endocytosed exogenous protein travel this common pathway. Hence, theHLA-A2, transferrin receptor, Na⁺ /K⁺ ATPase and bovine fetuin derivedpeptides would all encounter DR1 in a similar manner. Ii associates withnascent class II molecules in the endoplasmic reticulum (ER) (Jones etal., Mol. Immunol. 16:51-60 (1978)), preventing antigen binding untilthe class II/Ii complex arrives at an endocytic compartment (Roche andCresswell, Nature 345:615-618 (1990)), where Ii undergoes proteolysis(Thomas et al., J. Immunol. 140:2670-2675 (1988); Roche and Cresswell,Proc. Natl. Acad. Sci. USA 88:3150-3154 (1991)), thus allowing peptidebinding to proceed. Presumably, the Ii peptides bound to DR1 weregenerated at this step.

Synthetic peptides corresponding to five of the peptides reported inTable 1 were made and their relative binding affinities to DR1determined. The influenza A hemagglutinin peptide (HA) 307-319 (SEQ IDNO: 24) has been previously described as a high affinity, HLA-DR1restricted peptide (Roche and Cresswell, J. Immunol. 144:1849-1856(1990); Rothbard et al., Cell 52:515-523 (1988)), and was thus chosen asthe control peptide. "Empty" DR1 purified from insect cells expressingrecombinant DR1 cDNA was used in the binding experiments because of itshigher binding capacity and 10-fold faster association kinetics than DR1isolated from human cells (Stern and Wiley, Cell 68:465-477 (1992)). Allthe synthetic peptides were found to compete well (Ki <100 nM) againstthe HA peptide (Table 2). At first approximation, the Ii 107-120 peptide(SEQ ID NO: 156) had the highest affinity of all the competitor peptidesmeasured, equivalent to that determined for the control HA peptide. Inaddition to the Ki determinations, these peptides were found to conferresistance to SDS-induced α-β chain dissociation of "empty" DR1 whenanalyzed by SDS-PAGE, indicative of stable peptide binding(Sadegh-Nasseri and Germain, Nature 353:167-170 (1991); Dornmair et al.,Cold Spring Harbor Symp. Quant. Biol. 54:409-415 (1989); Springer etal., J. Biol. Chem. 252:6201-6207 (1977)). Neither of the two controlpeptides, β₂ m 52-64 (SEQ ID NO: 26) nor Ii 97-111 (SEQ ID NO: 25), wasable to either confer resistance to SDS-induced chain dissociation ofDR1 or compete with HA 307-319 (SEQ ID NO: 24) for binding to DR1; bothof these peptides lack the putative binding motif reported in this study(see below).

A putative DR1 binding motif based on the sequence alignments of thecore epitopes (the minimum length) of certain naturally processedpeptides is shown in Table 3. The peptides listed in this table includethose determined herein for HLA-DR1, as well as a number of peptidesidentified by others and known to bind DR1 (reference #6 in this tablebeing O'Sullivan et al., J. Immunol. 145:1799-1808, 1990; reference #17,Roche & Cresswell, J. Immunol. 144:1849-1856, 1990; reference #25,Guttinger et al., Intern. Immunol. 3:899-906, 1991; reference #27,Guttinger et al. EMBO J. 7:2555-2558, 1988; and reference #28, Harris etal., J. Immunol. 148:2169-2174, 1992). The key residues proposed in themotif are as follows: a positively charged group is located at the firstposition, referred to here as the index position for orientation (I); ahydrogen bond donor is located at I+5; and a hydrophobic residue is atI+9. In addition, a hydrophobic residue is often found at I+1 and/orI-1. Every naturally processed peptide sequenced from DR1 conforms tothis motif (with the exception of the HLA-A2 peptide 103-116 (SEQ ID NO:3) that lacks residue I+9). Because the putative motif is not placed ina defined position with respect to the first amino acid and because ofthe irregular length of bound peptides, it is impossible to deduce amotif from sequencing of peptide pools, as was done for class Imolecules (Falk et al., Nature 351:290-296 (1991)). The Ii 97-111peptide (SEQ ID NO: 25), a negative control peptide used in bindingexperiments, has the I and I+5 motif residues within its sequence, butis missing eight additional amino acids found in Ii 106-119 (SEQ ID NO:16) (Table 3C).

A sequence comparison of 35 previously described DR1 binding syntheticpeptides (O'Sullivan et al., J. Immunol. 145:1799-1808 (1990); Guttingeret al., Intern. Immunol. 3:899-906 (1991); Hill et al., J. Immunol.147:189-197 (1991); Guttinger et al., EMBO J. 7:2555-2558 (1988); Harriset al., J. Immunol. 148:2169-2174 (1992)) also supports this motif. Ofthe 35 synthetic peptides, 21 (60%) have the precise motif, nine (30%)contain a single shift at either I or I+9, and the remaining five (10%)have a single substitution at I (Table 3B and C). Interestingly, in thelatter peptides, a positive charge at I is always replaced by a largehydrophobic residue (Table 8C); a pocket has been described in class Imolecules that can accommodate this precise substitution (Latron et al.,Proc. Natl. Acad. Sci. USA 88:11325-11329 (1991)). Contributions by theother eight amino acids within the motif or the length of the peptidehave not been fully evaluated and may compensate for shifted/missingresidues in those peptides exhibiting binding. Evaluation of theremaining 117 non-DR1 binding peptides cited in those studies (whichpeptides are not included in Table 3) indicates that 99 (85%) of thesepeptides do not contain the DR1 motif proposed herein. Of the remaining18 peptides (15%) that do not bind to DR1 but which do contain themotif, 6 (5%) are known to bind to other DR allotypes; the remaining 12peptides may have unfavorable interactions at other positions whichinterfere with binding.

In contrast to the precise N-terminal cleavages observed in the previousstudy of six peptides bound to the mouse class II antigen termed I-A^(b)and five bound to mouse I-E^(b) (Rudensky et al., Nature 3563:622-627(1991)), the peptides bound to DR1 are heterogeneous at both the N- andC-termini. In contrast to peptides bound to class I molecules, which arepredominantly nonamers (Van Bleek and Nathenson, Nature 348:213-216(1990); Rotzschke et al., Nature 348:252-254 (1990); Jardetzky et al.,Nature 353:326-329 (1991); Hunt et al., Science 255:1261-1263 (1992)),class II peptides are larger and display a high degree of heterogeneityboth in length and the site of terminal truncation, implying that themechanisms of processing for class I and class II peptides aresubstantially different. Furthermore, the present results suggest thatclass II processing is a stochastic event and that a DR allotype maybind peptides of different lengths from a complex random mixture. Theheterogeneity observed may be solely due to protection of bound peptidesfrom further degradation. Thus, class II molecules would play an activerole in antigen processing (as previously proposed (Donermeyer andAllen, J. Immunol. 142:1063-1068 (1989)) by protecting the boundpeptides from complete degradation. Alternatively, the predominance of15mers bound to DR1 (as detected by both the MALD-MS and the yields ofsequenced peptides) could be the result of trimming of bound peptides.In any event, the absence of detectable amounts of peptides shorter than13 and longer than 25 residues suggests that there are lengthconstraints intrinsic either to the mechanism of peptide binding or toantigen processing. The predominance of peptides bound to DR1 that arederived from endogenously synthesized proteins, and particularlyMHC-related proteins, may result from the evolution of a mechanism forpresentation of self peptides in connection with the generation of selftolerance.

II. Other HLA-DR molecules.

The sequences of naturally processed peptides eluted from each of DR2,DR3, DR4, DR7 and DR8 are shown in Tables 4-8, respectively. In additionto those peptides shown in Table 4, it has been found that DR2 binds tolong fragments of HLA-DR2a β-chain and HLA-DR2b β-chain, correspondingto residues 1-126 or 127 of each of those proteins. Presumably, only ashort segment of those long fragments is actually bound within thegroove of DR2, with the remainder of each fragment protruding from oneor both ends of the groove. Table 9 gives sequences of DR1 from anothercell line which does not have wild-type Ar, but which has bound A2-likepeptides. Table 10 gives sequences of peptides eluted from DR4 and DR11molecules expressed in cells from a human spleen. These data demonstratethe great prevalence of self peptides bound, compared to exogenouspeptides. The data also show that the A2 and Ii peptides occurrepeatedly. In addition, certain of the Tables include peptides thatappear to derive from viral proteins, such as Epstein-Barr virus majorcapsid protein, which are likely to be present in the cells studied.

III. Peptide Delivery

Genetic Constructions.

In order to prepare genetic constructs for in vivo administration ofgenes encoding immunomodulatory peptides of the invention, the followingprocedure is carried out.

Overlapping synthetic oligonucleotides were used to generate the leaderpeptide/blocking peptide mini-genes illustrated in FIG. 3 by PCRamplification from human HLA-DRα and invariant chain cDNA templates.These mini-genes encode the Ii peptide fragments KMRMATPLLMQALPM (orIi₁₅ ; SEQ ID NO: 15) and LPKPPKPVSKMRMATPLLMQALPM (or Ii₂₄ ; SEQ ID NO:7). The resulting constructs were cloned into pGEM-2 (Promega Corp.) toform the plasmids pGEM-2-α-Ii₁₅ and pGEM-2-α-Ii₂₄, with an upstream T7promoter for use in the in vitro transcription/translation systemdescribed below.

For in vivo expression, each mini-gene was subsequently subcloned fromthe pGEM-2 derivatives into a transfection vector, pHβactin-1-neo(Gunning et al., (1987) Proc. Natl. Acad. Sci. U.S.A. 84:4831), to formthe plasmids pHβactin-α-Ii₁₅ and pHβactin-α-Ii₂₄. The insertedmini-genes are thus expressed in vivo from the constitutive/strong humanβ actin promoter. In addition, the mini-genes were subcloned from thepGEM-2 derivatives into the vaccinia virus recombination vector pSC11(S. Chakrabarti et al. (1985) Mol. Cell. Biol. 5, 3403-3409) to form theplasmids pSC11-α-Ii₁₅ and pSC11-α-Ii₂₄. Following recombination into theviral genome the inserted mini-genes are expressed from the strongvaccinia P₇.5 promoter.

Intracellular trafficking signals added to peptides.

Short amino acid sequences can act as signals to target proteins tospecific intracellular compartments. For example, hydrophobic signalpeptides are found at the amino terminus of proteins destined for theER, while the sequence KFERQ (SEQ ID NO: 153) (and other closely relatedsequences) is known to target intracellular polypeptides to lysosomes,while other sequences target polypeptides to endosomes. In addition, thepeptide sequence KDEL (SEQ ID NO: 152) has been shown to act as aretention signal for the ER. Each of these signal peptides, or acombination thereof, can be used to traffic the immunomodulatingpeptides of the invention as desired. For example, a construct encodinga given immunomodulating peptide linked to an ER-targeting signalpeptide would direct the peptide to the ER, where it would bind to theclass II molecule as it is assembled, preventing the binding of intactIi which is essential for trafficking. Alternatively, a construct can bemade in which an ER retention signal on the peptide would help preventthe class II molecule from ever leaving the ER. If instead a peptide ofthe invention is targeted to the endosomic compartment, this wouldensure that large quantities of the peptide are present when invariantchain is replaced by processed peptides, thereby increasing thelikelihood that the peptide incorporated into the class II complex isthe high-affinity peptides of the invention rather thannaturally-occurring, potentially immunogenic peptides. The likelihood ofpeptides of the invention being available incorporation into class IIcan be increased by linking the peptides to an intact Ii polypeptidesequence. Since Ii is known to traffic class II molecules to theendosomes, the hybrid Ii would carry one or more copies of the peptideof the invention along with the class II molecule; once in the endosome,the hybrid Ii would be degraded by normal endosomal processes to yieldboth multiple copies of the peptide of the invention or moleculessimilar to it, and an open class II binding cleft. DNAs encodingimmunomodulatory peptides containing targeting signals will be generatedby PCR or other standard genetic engineering or synthetic techniques,and the ability of these peptides to associate with DR molecules will beanalyzed in vitro and in vivo, as described below.

It is proposed that the invariant chain prevents class II molecules frombinding peptides in the ER and may contribute to heterodimer formation.Any mechanism that prevents this association would increase theeffectiveness of class II blockade. Therefore, a peptide correspondingto the site on Ii which binds to the class II heterodimer, orcorresponding to the site on either the α or β subunit of theheterodimer which binds to Ii, could be used to prevent this associationand thereby disrupt MHC class II function.

In Vitro Assembly.

Cell free extracts are used routinely for expressing eukaryotic proteins(Krieg, P. & Melton, D. (1984) Nucl. Acids Res. 12, 7057; Pelham, H. andJackson, R. (1976) Eur. J. Biochem. 67, 247). Specific mRNAs aretranscribed from DNA vectors containing viral RNA polymerase promoters(Melton, D. et al. (1984) Nucl. Acids Res. 12, 7035), and added tomicrococcal nuclease-treated cell extracts. The addition of ³⁵ Smethionine and amino acids initiates translation of the exogenous mRNA,resulting in labeled protein. Proteins may be subsequently analyzed bySDS-PAGE and detected by autoradiography. Processing events such assignal peptide cleavage and core glycosylation are initiated by theaddition of microsomal vesicles during translation (Walter, P. andBlobel, G. (1983), Meth. Enzymol., 96, 50), and these events aremonitored by the altered mobility of the proteins in SDS-PAGE gels.

The ability of peptides containing a signal peptide sequence to beaccurately processed and to compete with invariant chain for class IIbinding in the ER are assayed in the in vitro system described above.Specifically, DR1 α-and β-chain and invariant chain peptide constructsdescribed above are transcribed into mRNAs, which will be translated inthe presence of mammalian microsomal membranes. Association of the DRheterodimer with Ii is determined by immunoprecipitation with antiserato DR and Ii. Addition of mRNA encoding the peptide of the invention tothe translation reaction should result in a decreased level ofcoimmunoprecipitated Ii, and the concomitant appearance ofcoimmunoprecipitated peptide, as determined by SDS-PAGE on TRIS-Tricinegels. These experiments will provide a rapid assay system fordetermining the potential usefulness of a given blocking peptide as acompetitor for Ii chain binding in the ER. Those peptides of theinvention which prove to be capable of competing successfully with Ii inthis cell-free assay can then be tested in intact cells, as describedbelow.

In Vivo Assembly.

Human EBV-transformed B cell lines LG-2 and HOM-2 (homozygous forHLA-DR1) and the mouse B cell hybridoma LK35.2 are transfected witheither 50 kg of linearized pHβactin-a-Ii₁₅ or pHβactin-α-Ii₂₄ or (as acontrol) pHβactin-1-neo by electroporation (150 mV, 960 μF, 0.2 cmcuvette gap). Following electroporation, the cells are cultured inG418-free medium until total recovery (approximately 4 days). Eachpopulation is then placed under G418 selection until neomycin-expressingresistant populations of transfectants are obtained (approximately 1-2months). The resistant populations are subcloned by limiting dilutionand the clonality of stable transfectants determined by PCRamplification of blocking peptide mRNA expression.

Stable transfectants of LG-2 and HOM-2 carrying blocking peptidemini-genes or negative control vectors are grown in large-scale cultureconditions until 20 grams of pelleted cell mass is obtained. The HLA-DRexpressed by each transfectant is purified, and the bound peptiderepertoire (both from within the cell and from the cell surface)analyzed as described above. Successful demonstration of a reduction inthe total bound peptide diversity will be conclusive evidence ofintracellular delivery of immuno-modulatory peptides.

A second cell-based assay utilizes stable transfectants of LK35.2 cellscarrying blocking peptide mini-genes or negative control vectors; thesecells are used as APCs in T cell proliferation assays. Each transfectantis cultured for 24 hours in the presence of different dilutions of henegg lysozyme (HEL) and HEL-specific T cell hybridomas. The relativeactivation of the T cells present in each assay (as measured bylymphokine production) is determined using the publicly availablelymphokine dependent cell line CTLL2 in a ³ H-thymidine incorporationassay (Vignali et al. (1992) J.E.M. 175:925-932). Successfuldemonstration of a reduction in the ability of blocking peptideexpressing transfectants to present HEL to specific T cell hybridomaswill be conclusive evidence of intracellular delivery ofimmuno-modulatory peptides. Cells of the human TK⁻ cell line 143 (ATCC)are infected with vaccinia virus (strain WR, TK⁺) (ATCC), and two hourspostinfection, pSC11-α-Ii₁₅ or pSC11-α-Ii₂₄ or pSC11 is introduced intothe infected cells by calcium phosphate precipitation. TK⁻ recombinantsare selected for with bromodeoxyuridine at 25 μg/ml. Recombinant plaquesare screened by PCR for the presence of mini-gene DNA. Recombinant virusis cloned by three rounds of limiting dilution to generate pure clonalviral stocks.

In experiments analogous to the transfection experiments describedabove, recombinant vaccinia viruses encoding mini-genes or vector alonewill be used to infect large-scale cultures of the human EBV transformedB cell lines LG-2 and HOM-2. Following infection, the HLA-DR is purifiedand the bound peptide repertoire analyzed as described above. Areduction of the complexity of the bound peptide population and asignificant increase in the relative amount of Ii peptides bound areconclusive evidence that vaccinia can deliver blocking peptides to humanAPCs.

The same recombinant vaccinia viruses encoding mini-genes or vector willbe used to infect mice experiencing experimentally-induced autoimmunity.A number of such models are known and are referred in Kronenberg, Cell65:537-542 (1991).

Lirosomal Delivery of Synthetic Peptides or Mini-gene Constructs.

Liposomes have been successfully used as drug carriers and more recentlyin safe and potent adjuvant strategies for malaria vaccination in humans(Fries et al. (1992), Proc. Natl. Acad. Sci. USA 89:358). Encapsulatedliposomes have been shown to incorporate soluble proteins and deliverthese antigens to cells for both in vitro and in vivo CD8⁺ mediated CTLresponse (Reddy et al., J. Immunol. 148:1585-1589, 1992; and Collins etal., J. Immunol. 148:3336-3341, 1992). Thus, liposomes may be used as avehicle for delivering synthetic peptides into APCs.

Harding et al. (Cell (1991) 64, 393-401) have demonstrated that thetargeting of liposome-delivered antigen to either of two intracellularclass II-loading compartments, early endosomes and/or lysosomes, can beaccomplished by varying the membrane composition of the liposome:acid-sensitive liposomes were found to target their contents to earlyendosomes, while acid-resistant liposomes were found to deliver theircontents to lysosomes. Thus, the peptides of the invention will beincorporated into acid-sensitive liposomes where delivery to endosomesis desired, and into acid-resistant liposomes for delivery to lysosomes.

Liposomes are prepared by standard detergent dialysis ordehydration-rehydration methods. For acid-sensitive liposomes,dioleoylphosphatidylethanolamine (DOPE) and palmitoylhomocystein (PHC)are utilized, while dioleoylphospatidylcholine (DOPC) anddioleoylphosphatidylserine (DOPS) are used for the preparation ofacid-resistant liposomes. 10⁻⁵ mol of total lipid (DOPC/DOPS or DOPE/PHCat 4:1 mol ratios) are dried, hydrated in 0.2 ml of HEPES bufferedsaline (HBS) (150 mM NaCl, 1 mM EGTA, 10 mM HEPES pH 7.4) and sonicated.The lipid suspensions are solubilized by the addition of 0.1 ml of 1Moctylglucoside in HBS. The peptides to be entrapped are added to 0.2 mlof 0.6 mM peptide in 20% HBS. The mixture is then frozen, lyophilizedovernight, and rehydrated. These liposomes will be treated withchymotrypsin to digest any surface-bound peptide. Liposome delivery toEBV-transformed cell lines (as described above) will be accomplished by12-16 hour incubation at 37° C. HLA-DR will be purified from theliposome treated cells and bound peptide analyzed as above.

Alternatively, the liposomes are formulated with the DNA mini-geneconstructs of the invention, and used to deliver the constructs intoAPCs either in vitro or in vivo.

Human immunization will be carried out under the protocol approved byboth The Johns Hopkins University Joint Committee for ClinicalInvestigation and the Human Subject Research Review Board of the Officeof the Surgeon General of the U.S. Army (Fries et al. (1992), Proc.Natl. Acad. Sci. U.S.A. 89:358-362), using dosages described therein, orother dosages described in the literature for liposome-based delivery oftherapeutic agents.

Delivery via Immune-stimulating Complexes (ISCOMS).

ISCOMS are negatively charged cage-like structures of 30-40 nm in sizeformed spontaneously on mixing cholesterol and Quil A (saponin).Protective immunity has been generated in a variety of experimentalmodels of infection, including toxoplasmosis and Epstein-Barrvirus-induced tumors, using ISCOMS as the delivery vehicle for antigens(Mowat and Donachie) Immunology Today 12:383-385, 1991. Doses of antigenas low as 1 μg encapsulated in ISCOMS have been found to produce class Imediated CTL responses, where either purified intact HIV-1-IIIB gp 160envelope glycoprotein or influenza hemagglutinin is the antigen(Takahashi et al., Nature 344:873-875, 1990). Peptides are deliveredinto tissue culture cells using ISCOMS in a manner and dosage similar tothat described above for liposomes; the class II peptide binding ofdelivered peptides are then determined by extraction andcharacterization as described above. ISCOM-delivered peptides of theinvention which are effectively utilized by cultured cells are thentested in animals or humans.

In addition to delivery of the therapeutic synthetic peptides, ISCOMScould be constituted to deliver the mini-gene constructs to APCs, andthus serve as an alternative to the above-outlined vaccinia strategy.

Immunogenic Peptide Delivery (vaccines).

In addition to using the above-described intracellular delivery systemsto deliver nonimmunogenic self peptides with the specific aim ofdown-modulating the immune system (thus alleviating autoimmuneconditions), the delivery systems of the invention may alternatively beused as a novel means of vaccination, in order to stimulate a portion ofthe immune system of an animal. In the latter context, the deliverysystem is employed to deliver, into appropriate cells, DNA constructswhich express immunogenic, pathogen-derived peptides intended tostimulate an immune response against a specific pathogen. Because theantigenic peptide is produced inside the target cell itself, the vaccinemethod of the invention ensures that there is no circulating freeantigen available to stimulate antibody formation and thereby inducepotentially deleterious or inappropriate immunological reactions. Theimmune response stimulated by vaccines of the invention is, because thevaccines are targeted solely to APC's, limited to the T cell mediatedresponse, in contrast to standard vaccine protocols which result in amore generalized immune response. Although some of thepeptide-presenting APC's will initially be lysed by host T cells, suchlysis will be limited because, inter alia, the virus-based vaccine isnon-replicative, i.e., each carrier virus can infect only one cell.

The model antigen that will be used to perfect and test the system ofthe invention is hen egg lysozyme (HEL). It is arguably the most wellcharacterized protein for antigen presentation studies, to which thereare numerous monoclonal antibodies and class I- and class II-restrictedmouse T cell clones and hybridomas. The primary epitopes that will bestudied are the peptide HEL 34-45, as both monoclonal antibodies andCD4+T cell hybridomas are available, and peptide HEL 46-61, as bothclass I and class II-restricted T cell clones and hybridomas have beenraised and are publicly available. These two sequences are thus provenimmunogenic epitopes. Initially, four constructs encoding differentpolypeptides are analyzed: (a) whole, secreted HEL, (B) HEL 34-45, (c)HEL 46-61, and (d) HEL 34-61. The last three include a signal sequenceknown to be cleaved in these cells, e.g., IA^(k)(MPRSRALILGVLALTTMLSLCGG; SEQ ID NO: 274, which would result intargeting to the ER. All constructs are then subcloned into pHβApr-1neo. The methodology for making these constructs is similar to thatoutlined above. The constructs are introduced into appropriate APCs,e.g., LK35.2 cells, by means of a conventional eukaryotic transfectionor one of the delivery vehicles discussed above (e.g., vaccinia,liposomes, or ISCOMS). LK35.2 cells, which possess the mouse MHC ClassII restriction molecules IA^(k) and IE^(k), transfected with each of theconstructs are tested for their ability to stimulate the appropriateclass I and class II-restricted T cell hybridomas and clones usingstandard techniques. Whether class I stimulation is observed will dependon whether peptide trimming can occur in the ER, in order to produce an8-10-mer suitable for binding to class I molecules. If these constructsare ineffective for class I stimulation, they can be modified in orderto produce a more effective peptide for class I binding. If theseconstructs prove to be less effective for class II-restricted responses,they can be tagged with endosomal and/or lysosomal targeting sequencesas discussed in Section V.

The effectiveness of targeting signals used to direct immunogenicpeptides to particular intracellular organelles would be monitored usingelectron microscopic analysis of immunogold stained sections of thevarious transfectants. Rabbit anti-peptide antisera would be producedand affinity purified for this application. In addition, monoclonalantibody HF10, which recognizes HEL 34-45, will be used.

Once a construct is defined that can be effectively presented bytransfectants in vitro, its effectiveness in vivo will be determined.This can be tested by injection of the transfectants i.p. and/or s.c.into C3H/Balb/c Fl mice, or by injection of the construct incorporatedinto an appropriate delivery vehicle (e.g., liposome, ISCOMS,retrovirus, vaccinia). Optimal protocols and doses for such immunizinginjections can be determined by one of ordinary skill in the art, giventhe disclosures provided herein. Efficiency of immunization can betested by standard methods such as (a) proliferation of classII-restricted T cells in response to HEL pulsed APCs, (b) CTL responseto ⁵¹ Cr-labeled targets, and (c) serum antibody titre as determined byELISA.

Once the details of the vaccine delivery system of the invention areoptimized, constructs encoding peptides with useful immunizing potentialcan be incorporated into the system. Such peptides can be identified bystandard means now used to identify immunogenic epitopes onpathogen-derived proteins. For example, candidate peptides forimmunization may be determined from antibody and T cell analysis ofanimals infected with a particular pathogen. In order to obtain aprotective and effective anamnestic response, the peptides used forvaccination should ideally be those which are presented with the highestfrequency and efficiency upon infection. This could best be determinedby using the procedures outlined in the experimental section above toextract and characterize the peptides bound by MHC class II moleculesfrom infected cells. Given allelic restriction of immunogenic peptides(in contrast to the observed degenerate binding of self peptides ofinvention), a mini-gene encoding several immunogenic peptides willprobably be required to provide a vaccine useful for the entirepopulation. Vaccine administration and dosage are as currently employedto smallpox vaccination.

                                      TABLE 1                                     __________________________________________________________________________    LG-2/HLA-DR1 BINDING PEPTIDES                                                                                   SEQ                                         PROTEIN SOURCE                                                                          POSITION                                                                            SEQUENCE          ID NO.                                                                            LENGTH                                                                             FRACTION                                                                            MW  MASS                                                                                YIELD              __________________________________________________________________________    Pseudo HLA-A2                                                                           103-120                                                                             VGSDWRFLRGYHQYAYDG                                                                              1   18   DR1S-59                                                                             2190.4                                                                            2190.4                                                                              39.5                         103-117                                                                             VGSDWRFLRGYHQYA   2   15   DR1S-58                                                                             1855.0                                                                            1854.4                                                                              907.5                        103-116                                                                             VGSDWRFLRGYHQY    3   14   DR1S-58                                                                             1784.0                                                                            1783.6                                                                              53.3                         104-117                                                                             GSDWRFLRGYHQYA    4   14   DR1S-56                                                                             1755.3                                                                            1755.2                                                                              96.5                         105-117                                                                             SDWRFLRGYHQYA     5   13   DR1S-56                                                                             1698.2                                                                            1698.8                                                                              48.8               Invariant Chain                                                                          98-122                                                                             LPKPPKPVSKMRMATPLLMQALPMG                                                                       6   25   DR1S-88                                                                             2733.5                                                                            2734.5                                                                              40.5               (Ii)       98-121                                                                             LPKPPKPVSKMRMATPLLMQALPM                                                                        7   24   DR1S-88                                                                             2676.4                                                                            2675.9                                                                              80.8                          99-122                                                                             PKPPKPVSKMRMATPLLMQALPMG                                                                        8   24   DR1S-86                                                                             2620.2                                                                            2619.7                                                                              91.5                          98-120                                                                             LPKPPKPVSKMRMATPLLMQALP                                                                         9   23   DR1S-86                                                                             2545.2                                                                            2544.5                                                                              112.2                         99-121                                                                             PKPPKPVSKMRMATPLLMQALPM                                                                         10  23   DR1S-87                                                                             2563.2                                                                            2562.3                                                                              145.0                        100-121                                                                             KPPKPVSKMRMATPLLMQALPM                                                                          11  22   DR1S-87                                                                             2466.1                                                                            2465.8                                                                              101.5                         99-120                                                                             PKPPKPVSKMRMATPLLMQALP                                                                          12  22   DR1S-84                                                                             2432.0                                                                            2431.7                                                                              72.5                         100-120                                                                             KPPKPVSKMRMATPLLMQALP                                                                           13  21   DR1S-84                                                                             2334.9                                                                            2334.2                                                                              31.6                         100-120                                                                             PPKPVSKMRMATPLLMQALP                                                                            14  20   DR1S-86                                                                             2206.7                                                                            2207.4                                                                              89.8                         107-121                                                                             KMRMATPLLMQALPM   15  15   DR1S-88                                                                             1732.2                                                                            1731.9                                                                              178.5                        107-120                                                                             KMRMATPLLMQALP    16  14   DR1S-86                                                                             1601.0                                                                            1600.2                                                                              162.0              Na+/K+ ATPase                                                                           199-216                                                                             IPADLRIISANGCKVDNS                                                                              17  18   DR1S-56                                                                             1886.6                                                                            1885.8                                                                              48.8               Transferrin Recpt.                                                                      680-696                                                                             RVEYHFLSPYVSPKESP 18  17   DR1S-58                                                                             2035.3                                                                            2036.8                                                                              30.3               Bovine Fetuin                                                                           56-74 YKHTLNQIDSVKVWPRRPT                                                                             19  19   DR1S-51                                                                             2237.6                                                                            2236.5                                                                              69.0                         56-73 YKHTLNQIDSVKVWPRRP                                                                              20  18   DR1S-50                                                                             2338.7                                                                            2338.5                                                                              32.5               HLA-DR β-chain                                                                     43-61 DVGEYRAVTELGRPDAEYW                                                                             21  19   DR1S-51                                                                             2226.5                                                                            ?                        Carboxypeptidase E                                                                      101-115                                                                             EPGEPEFKYIGNMHG   22  15   DR1S-48                                                                             1704.9                                                                            1700.4*                                                                       ESI-MS                   __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    PEPTIDE BINDING TO HLA-DR1                                                                          Ki vs HA 307-319.sup.b                                  PEPTIDE.sup.a                                                                            SEQ ID NO.                                                                          LENGTH                                                                             nM       SDS-Resistance.sup.c nM                        __________________________________________________________________________    HLA-A2 103-117                                                                           2     15   49 ± 3                                                                              +                                              Ii 106-120 15    15   <10.sup. +                                              Ii 98-121  7     24   33 ± 5                                                                              +                                              Na+/K+ ATPase 199-216                                                                    17    18   68 ± 9                                                                              +                                              Transf. Recept. 680-696                                                                  18    17   <10      +                                              Bovine Fetuin 56-72                                                                      23    19   66 ± 18                                                                             +                                              HA 307-319 24    14   <10      +                                              Ii 97-111  25    15   >10.sup.4                                                                              -                                              β.sub.2 m 52-64                                                                     26    13   >10.sup.4                                                                              -                                              __________________________________________________________________________     .sup.a The first six entries correspond to peptides found associated with     HLADR1 and the sequences are shown in Table 1. Two control peptides were      also tested: β.sub.2 m 52-64, SDLSFSKDWSFYL (SEQ ID NO: 26), is from     human β-microglobulin and Ii 97-111, LPKPPKPVSKNRNAT (SEQ ID NO: 25)     is a truncated version of the longest invariant chain derived peptide         isolated from HLADR1. Peptides were synthesized using solidphase Fmoc         chemistry, deprotected and cleaved using standard methods, then purified      by RPC. Purified peptides were analzyed by mass spectrometry and              concentrations were determined by quantitative ninhydrin analysis.            .sup.b Inhibition constants (Ki) were measured as the concentration of        test peptide which inhibited 50% of the .sup.125 ILabeled HA 307-319          binding to "empty" HLADR1 produced in Sf9 insect cells (20). HA 307-319       was labeled using Na .sup.125 I and chloramineT and isolated by gel           filtration. Specific activity, determined by BCA assay (Pierce) and gamma     counting, was 26,000 cpm/pmol. 10 nM labeled peptide and 10 nM purified       HLADR1 were mixed with 10 different concentrations (10 nM to 10 μM) of     synthetic cold competitor peptide in phosphatebuffered saline, pH 7.2,        containing 1 mM EDTA, 1 mM PMSF, 0.1 mM iodoacetamide, and 3 mM NaN.sub.3     and incubated at 37° C. for 85 hours. Free and bound peptide were      separated by native gel electrophoresis (33) and bound radioactivity was      quantitated using a Fujix imaging plate analyzer (BAS 2000) after four        hour exposures on the phosphoimaging plates. Percent inhibition was           calculated as the ratio of backgroundcorrected radioactivity in the sampl     to backgroundcorrected radioactivity in a parallel sample containing no       competitor peptide. Under these conditions, Ki measurements <10 nM could      not be accurately determined.                                                 .sup.c The ability of the synthetic peptides to confer resistance to          SDSinduced chain dissociation of HLADR1 produced in insect cells was          determined as described (20). Briefly, 20 μM HLADR1 was incubated with     fivefold excess of synthetic peptide at 37° C. for 85 hours, in        phosphatebuffered saline (pH 7.2) with the protease inhibitor mixture         described above. After incubation, the samples were analyzed by SDS PAGE      with and without boiling prior to loading. Peptides which prevented           SDSinduced chain dissociation are indicated positive (+) and those that       did not negative (-).                                                    

                                      TABLE 3                                     __________________________________________________________________________    PUTATIVE HLA-DR1 PEPTIDE BINDING MOTIF                                        A PROTEIN SOURCE                                                                        PEPTIDE SEQUENCE SEQ ID NO.                                                                          LENGTH                                                                             POSITION                                                                            REFERENCE                         __________________________________________________________________________    HLA-A2    SDWKFLRGYHQYA    5     13   105-117                                                                             This study                        Invariant Chain                                                                         KMRMATPLLMQALP   16    14   106-119                                 Na+/K+ ATPase                                                                           IPADLRIISANGCKVDNS                                                                             17    18   199-216                                 Transferrin Receptor                                                                    RVEYHFLSPYVSPKESP                                                                              18    17   680-696                                 Bavine Fetuin                                                                           YKHTLNOIDSVKVWPRRP                                                                             20    18   56-73                                   B HEL     KVFGRCELAAAMKRHGLD                                                                             27    18    1-18 6                                           RNRCKGTDVQAWIRGCRL                                                                             28    18   112-129                                                                             6                                 β.sub.2 m                                                                          HPPHIEIQMLKNGKKI 29    16   31-46 6                                 PLA.sub.2 NELGRFKHTDACCRTH 30    16   19-34 6                                           SKPKVYQWFDLRKY   31    14   115-128                                                                             6                                 NASE      ATSTKKLHKEPATLIKAIDG                                                                           32    20   1-20  6                                           PATLIKAIDGDTVKLNYKGQ                                                                           33    20   11-30 6                                           DRVKLMYKGQPMTFRLLLVD                                                                           34    20   21-40 6                                           VAYVYKPNNTHEQHLKKSER                                                                           35    20   111-130                                                                             6                                 HIV p13   QKQEPIDKELYPLTSL 36    16    97-112                                                                             6                                 HIV p17   GARASVLSGGELDKWE 37    16    1-16 6                                 Influenza HA                                                                            RTLYQNVGTYVSVGTSTLNK                                                                           38    20   187-206                                                                             6                                 Influenza HA                                                                            PKYVKQNTLKLAT    24    13   307-319                                                                             17                                P. fatcip. p190                                                                         LKKLVFGYRKPLDNI  39    15   249-263                                                                             25                                P. fatcip. CS                                                                           KHIEQYLKKIKNS    40    13   329-341                                                                             27                                Chicken OVA                                                                             DVFKELKVHHANENIF 41    16   15-30 6                                 DR1 β chain                                                                        GDTRPRFLWQLKFECHFFNG                                                                           42    20    1-20 28                                          TERVRLLERCIYNOEESVRFDS                                                                         43    22   21-42 28                                          DLLEQRRMVDTYCRHNYGVGESFT                                                                       44    25   66-90 28                                p Cyt c   KAERADLIAYLKQATAK                                                                              45    17    88-104                                                                             6                                 Myelin basic prot.                                                                      GRTQDENPVVHFFKNIVTPRTPPP                                                                       46    24   75-98 6                                 C Influenza Matrix                                                                      PLKAEIAORLEDV    47    13   19-31 6                                 HIV p17   RQILGOLQPSLQTGSE 48    16   51-72 6                                 β.sub.2 M                                                                          IQVYSRHPPENGKPNI 49    16    7-22 6                                 PLA.sub.2 INTKCYKLEHPVTGCG 50    16    85-100                                                                             6                                 P. falcip. p190                                                                         YKLNFYFDLLRAKL   51    14   211-224                                                                             25                                          IDTLKXNENIKEL    52    13   338-350                                                                             25                                DR1 β chain                                                                        DVGEYRAVTELGRPDAEYWN                                                                           53    20   43-62 28                                HIV p17   ERFAVNPGLLETSEGC 54    16   41-56 6                                 HEL       DNYRGYSLGNWVCAAKFESNFTQ                                                                        55    23   20-42 6                                 NASE      EALVRQGLAKVAYVYKPNNT                                                                           56    20   101-120                                                                             6                                 HIV p25   PIVQNLOGOMVHQAIS 57    16    1-16 6                                           SALSEGATPQDLNTML 58    16   41-56 6                                 β.sub.2 m                                                                          SFYILAHTEFTPTETD 59    16   61-76 6                                 PLA.sub.2 KMYFNLINTKCYKLEH 60    16   79-94 6                                 __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    MST/HLA-DR2 BINDING PEPTIDES                                                  PROTEIN SOURCE                                                                           POSITION                                                                            SEQUENCE           SEQ ID NO.                                                                          LENGTH                                                                             FRACTION                                                                            MW  MASS                 __________________________________________________________________________                                                             SPEC                 Pseudo HLA-A2                                                                            103-120                                                                             VGSDWRFLRGYHQYAYDG 1     18   DR2-3-57                                                                            2190.4                                                                            2189.0                          103-119                                                                             VGSDWRFLRGYHQYAYAD 61    17   DR2-3-57                                                                            2133.3                                                                            2131.8                          104-119                                                                             GSDWRFLRGYHQYAYD   62    16   DR2-3-56                                                                            2034.3                                                                            2040.4                          103-117                                                                             VGSDWRFLRGYHQYA    2     15   DR2-3-56                                                                            1855.0                                                                            1858.5                          103-116                                                                             VGSDWRFLRGYHQY     3     14   DR2-3-56                                                                            1784.0                                                                            1786.3                          104-117                                                                             GSDWRFLRGYHQYA     4     14   DR2-3-55                                                                            1755.3                                                                            1755.0*                         105-117                                                                             SDWRFLRGYHQYA      5     13   DR2-3-56                                                                            1698.2                                                                            1702.6               Invariant Chain                                                                           98-121                                                                             LPKPPKPVSKMRMATPLLMQALPM                                                                         7     24   DR2-3-70                                                                            2676.4                                                                            2675.0*              (Ii)        99-121                                                                             PKPPKPVSKMRMATPLLMQALPM                                                                          10    23   DR2-3-70                                                                            2563.2                                                                            2562.0*                         100-121                                                                             KPPKPVSKMRMATPLLMQALPM                                                                           11    22   DR2-3-70                                                                            2466.1                                                                            2465.0*                          99-120                                                                             PKPPKPVSKMRMATPLLMQALP                                                                           12    22   DR2-3-66                                                                            2432.0                                                                            2437.0                          100-120                                                                             KPPKPVSKMRMATPLLMQALP                                                                            13    21   DR2-3-66                                                                            2334.9                                                                            2340.0                          101-120                                                                             PPKPVSKMRMATPLLMQALP                                                                             63    20   DR2-3-70                                                                            2206.7                                                                            2207.0*                         107-125                                                                             KMRMATPLLMQALPMGALP                                                                              64    19   DR2-3-71                                                                            2070.5                                                                            2074.3                          107-121                                                                             KMRMATPLLMQALPM    15    15   DR2-3-70                                                                            1732.2                                                                            1732.0*              HLA-DQ α-chain                                                                      97-119                                                                             NIVIKRSNSTAATNEVPEVTVFS                                                                          158   23   DR2-3-44                                                                            2476.8                                                                            2478.1                           97-112                                                                             NIVIKRSNSTMTNEV    159   16   DR2-3-41                                                                            1716.9                                                                            1717.0               HLA-DQ β-chain                                                                      42-59 SDVGVYRAVTPQGRPDAE 160   18   DR2-3-41                                                                            1917.1                                                                            1920.5                          43-59 DVGVYRAVTPQGRPDAE  161   17   DR2-3-41                                                                            1830.0                                                                            1833.3                          43-57 DVGVYRAVTPQGRPD    162   15   DR2-3-41                                                                            1629.8                                                                            1632.9               HLA-DR α-chain                                                                     182-194                                                                             APSPLPETTENW       163   13   DR2-3-36                                                                            1353.5                                                                            1362.0                          182-198                                                                             APSPLPETTENVVCALG  164   17   DR2-3-41                                                                            1697.9                                                                            1701.0               (MET) Kinase-relate                                                                      59-81 EHHIFLGATNYIYVLNEEDLQKV                                                                          65    23   DR2-3-65                                                                            2746.1                                                                            2746.6               trasforming protein                                                           Guanylate-bind.                                                                          434-450                                                                             QELKNKYYQVPRKGIQA  66    17   DR2-3-71                                                                            2063.4                                                                            2074.3               Mannose-bind. prot.                                                                       74-193                                                                             IQNLIKEEAFLGITDEKTEG                                                                             67    20   DR2-3-70                                                                            2248.5                                                                            2248.0*              Apolipoprotein B-100                                                                     1200-1220                                                                           FPKSLHTYANILLDRRVPQTD                                                                            165   21   DR2-3-61                                                                            2484.8                                                                            2490.9                          1200-1218                                                                           FPKSLHTYANILLDRRVPQ                                                                              166   19   DR2-3-61                                                                            2268.6                                                                            2276.7               Potassium channel prot                                                                   173-190                                                                             DGILYYYQSGGRLRRPVN 167   18   DR2-3-61                                                                            2127.4                                                                            2132.6                          173-189                                                                             DGILYYYQSGGRLRRPV  168   17   DR2-3-61                                                                            2013.3                                                                            2018.1               Fibronectin receptor                                                                     586-616                                                                             LSPIHIALNFSLDPQAPVDSHGLRPALHYQ                                                                   169   30   DR2-3-61                                                                            3307.7                                                                            3313.1               Factor VIII                                                                              1175-1790                                                                           LWDYGNSSSPHVLRNR   170   16   DR2-3-44                                                                            1918.2                                                                            1921.7               HLA-DR2b β-chain                                                                     94-111                                                                             RVQPKVTVYPSKTQPLQH 72    18   DR2-3-39                                                                            2106.5                                                                            2114.                            94-108                                                                             RVQPKVTVYPSKTQP    73    15   DR2-3-39                                                                            1728.3                                                                            1730.6                                                                        ESI-MS*                                                                       MALD-MS              __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    WT-20/HLA-DR3 NATURALLY PROCESSED PEPTIDES                                    Protein Source                                                                           Position                                                                            Sequence           SEQ ID NO.                                                                          Length                                                                             Fraction                                                                            MW  Mass                 __________________________________________________________________________                                                             Spec.                Pseudo HLA-A2                                                                            103-117                                                                             VGSDWRFLRGYHQYA    2     15   DR3-2-63                                                                            1855.0                                                                            1863.9               HLA-A30    28-?  VDDTQFVRFDSDAASQ. . .                                                                            171   ?    DR3-2-55                                                                            ?   ?                    HLA-DR α-chain                                                                     111-129                                                                             PPEVTVLTNSPVELREPNV                                                                              172   19   DR3-2-55                                                                            2090.4                                                                            2093.3                          111-128                                                                             PPEVTVLTNSPVELREPN 173   18   DR3-2-55                                                                            1991.2                                                                            1989.8               HLA-DR β-chain                                                                      1-?   GDTRPRFLEYSTSECHFF 79    18   DR3-2-73                                                                            ?   ?                    Acetylcholine recept.                                                                    289-304                                                                             VFLLLLADKVPETSLS   174   16   DR3-2-65                                                                            1745.1                                                                            1750.1               Glucose-transport                                                                        459-474                                                                             TFDEIASGFRQGGASQ   175   16   DR3-2-55                                                                            1670.8                                                                            1672.6               Sodium channel prot.                                                                     384-397                                                                             YGYTSYDTFSWAFL     176   14   DR3-2-41                                                                            1720.8                                                                            1720.5               Invariant chain                                                                           98-120                                                                             LPKPPKPVSKMRMATPLLMQALP                                                                          9     23   DR3-2-73                                                                            2545.2                                                                            2554.0               (Ii)        99-120                                                                             PKPPKPVSKMRMATPLLMQALP                                                                           12    22   DR3-2-73                                                                            2432.0                                                                            2441.4                          100-120                                                                             KPPKPVSKMRMATPLLMQALP                                                                            13    21   DR3-2-73                                                                            2334.9                                                                            2345.3                           32-150                                                                             ATKYGNMTEDHVMHLLQNA                                                                              177   19   DR3-2-69                                                                            2173.4                                                                            2179.3               CD45       1071-1084                                                                           GQVKKNNHQEDKIE     178   14   DR3-2-41                                                                            1666.8                                                                            1667.0               ICAM-2     64-76 LNKILLDEQAQWK      179   13   DR3-2-51/52                                                                         1598.9                                                                            1602.4               Interferon γ-receptor                                                              128-147                                                                             GPPKLDIRKEEKQIMIDIFH                                                                             180   21   DR3-2-77                                                                            2505.0                                                                            2510.3                          128-148                                                                             GPPKLDIRKEEKQIMIDIFHP                                                                            181   20   DR3-2-77                                                                            2407.8                                                                            2412.4               IP-30      38-59 SPLQALDFFGNGPPVNYKTGNL                                                                           182   22   DR3-2-77                                                                            2505.0                                                                            2510.3                          38-57 SPLQALDFFGNGPPVNYKTG                                                                             183   20   DR3-2-77                                                                            2122.4                                                                            2124.2               Cytochrome-b5 reduc.                                                                     155-172                                                                             GKFAIRPDKKSNPIIRTV 184   18   DR3-2-51/52                                                                         2040.4                                                                            2043.2               EBV membrane antigen                                                                     592-606                                                                             TGHGARTSTEPTIDY    185   15   DR3-2-41                                                                            1593.6                                                                            1592.1               GP220                                                                         EBV tegument protein                                                                     1395-1407                                                                           KELKRQYEKKLRQ      186   13   DR3-2-51/52                                                                         1747.1                                                                            1749.8               membrane p140                                                                 Apolipoprotein                                                                           1276-1295                                                                           NFLKSDGRIKYTLNKNSLK                                                                              74    20   DR3-2-63                                                                            2352.9                                                                            2360.0               B-100 (Human)                                                                            1273-1292                                                                           IPDNLFLKSDGRIKYTLNKN                                                                             191   20   DR3-2-65                                                                            2349.7                                                                            2354.6                          1273-1291                                                                           IPDNLFLKSDGRIKYTLNK                                                                              75    19   DR3-2-63                                                                            2235.5                                                                            2245.1                          1273-1290                                                                           IPDNLFLKSDGRIKYTLN 192   18   DR3-2-65                                                                            2107.4                                                                            2096.6                          1273-1289                                                                           IPDNLFLKSDGRIKYTL  193   17   DR3-2-65                                                                            1993.3                                                                            2000.8                          1276-1291                                                                           NLFLKSDGRIKYTLNK   76    16   DR3-2-60                                                                            1910.2                                                                            1911.4                          1276-1290                                                                           NLFLKSDGRIKYTLN    77    15   DR3-2-60                                                                            1782.1                                                                            1785.9                          1207-1224                                                                           YANILLDRRVPQTDMTF  78    17   DR3-2-63                                                                            2053.3                                                                            2059.1                          1794-1810                                                                           VTTLNSDLKYNALDLTN  194   17   DR3-2-69                                                                            1895.1                                                                            1896.5                                                                        MALD-MS              __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________    PRIESS/HLA-DR4 NATURALLY PROCESSED PEPTIDES                                   PROTEIN SOURCE                                                                           POSITION                                                                            SEQUENCE           SEQ ID NO.                                                                          LENGTH                                                                             FRACTION                                                                            MW  MASS                 __________________________________________________________________________                                                             SPEC                 Ig Kappa Chain                                                                            88-208                                                                             KHKVYACEVTHQGLSSPVTKS                                                                            80    21   DR4-2-45                                                                            2299.6                                                                            2304.0               C region (Human                                                                          188-207                                                                             KHKVYACEVTHQGLSSPVTK                                                                             81    20   DR4-2-41                                                                            2212.5                                                                            2213.0                          189-206                                                                             HKVYACEVTHQGLSSPVT 82    18   DR4-2-43                                                                            1955.5                                                                            1952.1                          188-204                                                                             KHKVYACEVTHQGLSSP  83    17   DR4-2-45                                                                            1883.1                                                                            1882.8                          187-203                                                                             EKHKVYACEVTHQGLSS  84    17   DR4-2-45                                                                            1915.1                                                                            1922.5                          188-203                                                                             KHKVYACEVTHQGLSS   85    16   DR4-2-54                                                                            1787.0                                                                            1787.0                          189-204                                                                             HKVYACEVTHQGLSSP   86    16   DR4-2-47                                                                            1755.0                                                                            1767.8                          187-202                                                                             EKHKVYACEVTHQGLS   87    16   DR4-2-43                                                                            1828.0                                                                            1822.8                          188-202                                                                             KHKVYACEVTHQGLS    88    15   DR4-2-51                                                                            1699.9                                                                            1708.3                          189-203                                                                             HKVYACEVTHQGLSS    89    15   DR4-2-45                                                                            1657.8                                                                            1667.0                          187-200                                                                             EKHKVYACEVTHQG     90    14   DR4-2-51                                                                            1628.8                                                                            1632.6               HLA-DR α-chain                                                                     182-198                                                                             APSPLPETTENVVCALG  91    17   DR4-2-43                                                                            1697.9                                                                            1700                 HLA-A2     28-50 VDDTQFVRFDSDAASQRNEPRAP                                                                          195   23   DR4-2-58                                                                            2638.6                                                                            2641.5                          28-48 VDDTQFVRFDSDAASQRNEPR                                                                            92    21   DR4-2-56                                                                            2470.6                                                                            2472.9                          28-47 VDDTQFVRFDSDAASQRNEP                                                                             93    20   DR4-2-59                                                                            2314.5                                                                            2319.3                          28-46 VDDTQFVRFDSDAASQRNE                                                                              94    19   DR4-2-54                                                                            2217.2                                                                            2218.7                          30-48 DTQFVRFDSDAASQRNEPR                                                                              95    19   DR4-2-55                                                                            2256.4                                                                            2263.2                          31-49 TQFVRFDSDAASQRNEPRA                                                                              96    19   DR4-2-56                                                                            2212.4                                                                            2211.5                          28-44 VDDTQFVRFDSDAASQR  97    17   DR4-2-55                                                                            1957.0                                                                            1963.1                          31-47 TQFVRFDSDAASQRNEP  98    17   DR4-2-56                                                                            1985.1                                                                            1987.5                          31-45 TQFVRFDSDAASQRN    99    15   DR4-2-54                                                                            1758.9                                                                            1761.0                          31-42 TQFVRFDSDAAS       100   12   DR4-2-54                                                                            1343.4                                                                            1343.3               HLA-C      28-50 VDDTQFVRFDSDAASPRGEPRAP                                                                          101   23   DR4-2-56                                                                            2533.7                                                                            2536.7                          31-52 TQFVRFDSDAASPRGEPRAPWV                                                                           102   22   DR4-2-54                                                                            2489.7                                                                            2491.5                          28-48 VDDTQFVRFDSDAASPRGEPR                                                                            103   21   DR4-2-54                                                                            2365.5                                                                            2368.1                          28-47 VDDTQFVRFDSDAASPRGEP                                                                             104   20   DR4-2-56                                                                            2209.3                                                                            2211.5                          28-46 VDDTQFVRFDSDAASPRGE                                                                              105   19   DR4-2-56                                                                            2112.2                                                                            2113.9               HLA-Cw9    28-45 VDDTQFVRFDSDAASPRG 106   18   DR4-2-56                                                                            1983.1                                                                            1987.5                          31-48 TQFVRFDSDAASPRGEPR 107   18   DR4-2-52                                                                            2036.2                                                                            2041.5                          28-44 VDDTQFVRFDSDAASPR  108   17   DR4-2-55                                                                            1926.6                                                                            1931.7                          30-46 DTQFVRFDSDAASPRGE  109   17   DR4-2-52                                                                            1897.9                                                                            1901.6                          31-44 TQFVRFDSDAASPR     110   14   DR4-2-52                                                                            1596.7                                                                            1603.7                          31-42 TQFVRFDSDAAS       111   12   DR4-2-54                                                                            1343.4                                                                            1343.3               HLA-C      130-150                                                                             LRSWTAADTMQITQRKWEAA                                                                             112   21   DR4-2-56                                                                            2374.6                                                                            2376.4                          129-147                                                                             DLRSWTAADTMQITQRKW 197   19   DR4-2-58                                                                            2218.4                                                                            2220.1                          130-147                                                                             LRSWTAADTMQITQRKW  198   18   DR4-2-58                                                                            2103.3                                                                            2105.0                          129-145                                                                             DLRSWTAADTMQITQR   113   17   DR4-2-59                                                                            1904.5                                                                            1908.7                          129-144                                                                             DLRSWTAADTMQITQ    114   16   DR4-2-59                                                                            1747.9                                                                            1752.3                          129-143                                                                             DLRSWTAADTMQIT     115   15   DR4-2-59                                                                            1619.7                                                                            1622.2               HLA-Bw62   129-150                                                                             DLSSWTAADTMQITQRKWEAA                                                                            199   22   DR4-2-65                                                                            2420.6                                                                            2422.7                          129-145                                                                             DLSSWTAADTMQITQR   116   17   DR4-2-60                                                                            1834.9                                                                            1838.1                          129-146                                                                             DLSSWTAADTMQITQRK  200   18   DR4-2-65                                                                            1963.1                                                                            1966.3                          129-148                                                                             DLSSWTAADTMQITQRKWE                                                                              117   20   DR4-2-66                                                                            2278.4                                                                            2284.6               VLA-4      229-248                                                                             GSLFVYNITTNKYKAFLDKQ                                                                             201   20   DR4-2-65                                                                            2350.7                                                                            2352.6                          229-244                                                                             GSLFVYNITTNKYKAF   202   16   DR4-2-65                                                                            1866.1                                                                            1868.2               PAI-1      261-281                                                                             AAPYEKEVPLSALTNILSAQL                                                                            203   21   DR4-2-65                                                                            2228.5                                                                            2229.5                          261-278                                                                             AAPYEKEVPLSALTNILS 204   18   DR4-2-65                                                                            1916.2                                                                            1917.4               Cathepein C                                                                              151-167                                                                             YDHNFVKAINADQKSWT  118   17   DR4-2-70                                                                            2037.2                                                                            2039.6               (Rat Homologue)  I                  119              2035.3                              151-166                                                                             YDHNFVKAINADQKSW   120   16   DR4-2-70                                                                            1936.1                                                                            1937.7                                I                  121              1934.2                   Bovine Hemoglobin                                                                        26-41 AEALERNFLSFPTTKT   205   16   DR4-2-78                                                                            1842.1                                                                            1836.1               HLA-DQ3.2 β-chain                                                                   24-38 SPEDFVYQFKGHCYF    206   15   DR4-2-78                                                                            1861.1                                                                            1861.7               HLA-DR β-chain                                                                      1-?   GDTRPRFLEQVKHE. . .                                                                              122   14   DR4-2-72                                                                            1711.9                   IG Heavy chain                                                                           121-? GVYFYLQWGRSTLVSVS. . .                                                                           123   (?)  DR4-2-6                                                                             ?   ?                                                                             MALD-MS              __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    MANW/HLA-DR7 NATURALLY PROCESSED PEPTIDES                                     PROTEIN SOURCE                                                                           POSITION                                                                            SEQUENCE           SEQ ID NO.                                                                          LENGTH                                                                             FRACTION                                                                            MW  MASS                 __________________________________________________________________________                                                             SPEC                 Pseudo HLA-A2                                                                            105-124                                                                             SDWRFLRGYHQYAYDGKDYI                                                                             207   20   DR1-2-61                                                                            2553.8                                                                            2556.5                          103-120                                                                             VGSDWRFLRGYHQYAYDG 1     18   DR7-2-63                                                                            2190.4                                                                            2194                            103-117                                                                             VGSDWRFLRGYHQYA    2     15   DR1-2-63                                                                            1855.0                                                                            1860                            104-117                                                                             GSDWRFLRGYHQYA     208   14   DR7-2-61                                                                            1755.9                                                                            1760.8                          104-116                                                                             GSDWRFLRGYHQY      209   13   DR7-2-61                                                                            1684.8                                                                            1687.6                          105-117                                                                             SOWRFLRGYHQYA      210   13   DR7-2-61                                                                            1698.9                                                                            1704.1               HLA-A29    234-253                                                                             RPAGDGTFQKWASVVVPSGQ                                                                             124   20   DR7-2-66                                                                            2087.3                                                                            2092                            234-249                                                                             RPAGDGTFQKWASVVV   125   16   DR7-2-63                                                                            1717                                                                              1718                            237-258                                                                             GDGTFQKWASVVVPSGQEQRYT                                                                           126   22   DR7-2-66                                                                            2436                                                                              2440                            237-254                                                                             GDGTFQKWASWVPSGQE  127   18   DR7-2-66                                                                            1892.3                                                                            1892                            239-252                                                                             GTFQKWASVVVPSG     128   14   DR7-2-66                                                                            1462                                                                              1465                            239-253                                                                             GTFQKWASWVPSGQ     129   15   DR7-2-66                                                                            1718                                                                              1721                            239-261                                                                             GTFQKWASWVPSGQEQRYTCHV                                                                           130   23   DR7-2-66                                                                            2603                                                                              2606                 HLA-B44    83-99 RETQISKTNTQTYRENL  211   17   DR7-2-35                                                                            2082.3                                                                            2086.1                          83-98 RETQISKTNTQTYREN   212   16   DR7-2-35                                                                            1969.1                                                                            1971.1                          83-97 RETQISKTNTQTYRE    213   15   DR7-2-35                                                                            1855.0                                                                            1857.3               HLA-DR α-chain                                                                     101-126                                                                             RSNYTPITNPPEVTVLTNSPVELREP                                                                       214   26   DR7-2-35                                                                            2924.2                                                                            2926.9                          58-78 GALANIAVDKANLEIMTKRSN                                                                            131   21   DR7-2-66                                                                            2229.5                                                                            2221                            182-200                                                                             APSPLPETTENVVCALGLTV                                                                             215   20   DR7-2-42                                                                            1912.2                                                                            1917.7               HLA-DQ β-chain                                                                      179-? SLQSPITVEWRAQSESAQSKNLSGIGGFVL                                                                   216   ?    DR7-2-35                                                                            ?   ?                    4F2 Cell-surface                                                                         318-338                                                                             VTQYLNATGNRWCSWSLSQAR                                                                            217   21   DR7-2-71                                                                            2441.7                                                                            2445.1               antigen heavy chain                                                                      318-334                                                                             VTQYLNATGNRWCSWSL  218   11   DR7-2-71                                                                            1999.2                                                                            2001.9               LIF receptor                                                                             854-866                                                                             TSILCYRKREWIK      219   13   DR7-2-35                                                                            1696.0                                                                            1700.8               Ig kappa chain C reg.                                                                    188-201                                                                             KHKVYACEVTHQGL     220   14   DR7-2-61                                                                            1612.9                                                                            1615.6                          188-200                                                                             KHKVYACEVTHQG      221   13   DR7-2-61                                                                            1498.7                                                                            1501.0               Invariant Chain                                                                           99-120                                                                             PKPPKPVSICMRMATPLLMQALP                                                                          12    22   DR7-2-72                                                                            2432.0                                                                            2436.6               (Ii)       100-120                                                                             KPPKPVSKMRMATPLLMQALP                                                                            13    21   DR7-2-72                                                                            2334.9                                                                            2339.7               K channel protein                                                                        492-516                                                                             GDMYPKTWSGMLVGALCALAGVLTI                                                                        222   25   DR7-2-71                                                                            2567.1                                                                            2567.3               Heat shock cognate                                                                       38-54 TPSYVAFTDTERLIGDA  132   17   DR7-2-69                                                                            1856.0                                                                            1856.6               71 KD protein                             17   DR7-2-72                                                                            1856.0                                                                            1857.0                          38-52 TPSYVAFTDTERLIG    133   15   DR7-2-69                                                                            1669.8                                                                            1671.9               Complement C9                                                                            465-483                                                                             APVLISQKLSPIYNLVPVK                                                                              223   19   DR7-2-61                                                                            2079.5                                                                            2083.9               Thromboxane-A                                                                            406-420                                                                             PAFRFTREMQDCEV     224   15   DR7-2-71                                                                            1739.9                                                                            1743.0               synthase                                                                      EBV major capsid prot                                                                    1264-1282                                                                           VPGLYSPCRAFFNKEELL 225   18   DR7-2-54                                                                            2082.4                                                                            2081.2                          1264-1277                                                                           VPGLYSPCRAFFNK     226   14   DR7-2-54                                                                            1597.9                                                                            1598.6               Apolipoprotein B-100                                                                     1586-1608                                                                           KVDLTFSKQHALLCSDYQADYES                                                                          227   23   DR7-2-54                                                                            2660.9                                                                            2662.5                          1586-1600                                                                           KVDLTFSKQHALLCS    228   15   DR1-2-54                                                                            1689.0                                                                            1687.7                          1942-1954                                                                           FSHDYRGSTSHRL      229   13   DR7-2-42                                                                            1562.7                                                                            1567.5                          2077-2089                                                                           LPKYFEKKRNTIL      230   13   DR7-2-61                                                                            1650.0                                                                            1653.8                                                                        MALD-MS              __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________    23.1/HLA-DRδ NATURALLY PROCESSED PEPTIDES                               PROTEIN SOURCE                                                                           POSITION                                                                            SEQUENCE           SEQ. ID NO.                                                                         LENGTH                                                                             FRACTION                                                                            MW  MASS                 __________________________________________________________________________                                                             SPEC                 HLA-DR α-chain                                                                     158-180                                                                             SETVFLPREDHLFRKFHYLPFLP                                                                          231   23   DR8-3-59                                                                            2889.3                                                                            2889.0                          182-198                                                                             APSPLPETTENVVCALG  232   17   DR8-3-41                                                                            1697.9                                                                            1704.3               HLA-DR β-chain                                                                      1-?   GDTRPRFLEYSTGECYFFNGTERV                                                                         233   ?    DR8-3-75                                                                            --  --                   HLA-DP β-chain                                                                      80-92 RHNYELDEAVTLQ      234   13   DR8-3-76                                                                            1587.7                                                                            1591.3               LAN Blast-1 with                                                                          88-108                                                                             DPQSGALYISKVQKEDNSTYI                                                                            235   21   DR8-3-54                                                                            2543.6                                                                            2549.1               N-acetyglucosamine                                                                        92-108                                                                             GALYISKVQKEDNSTYI  236   17   DR8-3-52                                                                            2116.1                                                                            2118.0                          129-146                                                                             DPVPKPVIKIEKIEDHDD 237   18   DR8-3-57                                                                            2081.4                                                                            2085.7                          129-143                                                                             DPVPKPVIKIEKIED    238   15   DR8-3-57                                                                            1720.0                                                                            1724.9               Ig kappa chain                                                                           63-80 FTFTISRLEPEDFAVYYC 239   18   DR8-3-57                                                                            2201.5                                                                            2203.6                          63-77 FTFTISRLEPEDFAV    240   15   DR8-3-57                                                                            1772.0                                                                            1777.0               LAR protein                                                                              1302-1316                                                                           DPVENRRLNYQTPG     241   14   DR8-3-76                                                                            1675.9                                                                            1679.8               LIF receptor                                                                             709-726                                                                             YQLLRSNIGYIEELAPIV 242   18   DR8-3-66                                                                            2108.5                                                                            2112.0               IFN-α receptor                                                                     271-287                                                                             GNHLYK QIPDCENVK   243   17   DR8-3-66                                                                            2072.4                                                                            2075.1               Interleukin-B                                                                            169-188                                                                             LPFFLFRQAYHPNNSSPVCY                                                                             244   20   DR8-3-59                                                                            2400.7                                                                            2402.5               receptor                                                                      Metalloproteinase                                                                        187-214                                                                             QAKFFACIKRSDGSCAWYRGAAPPKQEF                                                                     245   28   DR8-2-63                                                                            3161.6                                                                            3164.9               inhibitor 2                                                                              187-205                                                                             QAKFFACIKRSDGSCAWYR                                                                              246   19   DR8-3-63                                                                            2235.5                                                                            2233.6               Metalloproteinase                                                                        101-118                                                                             NRSEEFLIAGKLQDGLLH 134   18   DR8-3-66                                                                            2040.3                                                                            2042.9               inhibitor 1                                                                              101-117                                                                             SEEFLIAGKLQDGLL    135   16   DR8-3-70                                                                            1789.0                                                                            1799.9                          103-117                                                                             SEEFLIAGKLQDGLL    247   15   DR8-3-72                                                                            1632.9                                                                            1646.0                          101-112                                                                             NRSEEFLIAGKL       248   12   DR8-3-66                                                                            1376.6                                                                            1381.8               Cathepsin E                                                                               89-112                                                                             QNFTVIFDTGSSNLWVPSVYCTSP                                                                         249   24   DR8-3-59                                                                            2662.9                                                                            2664.4               Cathepsin S                                                                              189-205                                                                             TAFQYIIDNKGIDSDAS  68    17   DR8-3-63                                                                            1857.9                                                                            1857.1               Cystatin SN                                                                              41-58 DEYYRRLLRVLRAREQIV 250   18   DR8-3-63                                                                            2348.7                                                                            2348.0               Tubulin α-1 chain                                                                  207-223                                                                             EAIYDICRRNLDIERPT  251   17   DR8-3-63                                                                            2077.3                                                                            2078.3                          207-219                                                                             EAIYDICRRNLDI      252   13   DR8-3-63                                                                            1593.8                                                                            1595.1               Myosin β-heavy chain                                                                1027-1047                                                                           HELEKIKKQVEQEKCEIQAAL                                                                            253   21   DR8-3-59                                                                            2493.9                                                                            2494.0               Ca release channel                                                                       2614-2623                                                                           RPSMLQHLLR         254   10   DR8-3-68                                                                            1250.5                                                                            1254.8               CD35       359-380                                                                             DDFMGQLLNGRVLFPVNLQLGA                                                                           255   22   DR8-3-72                                                                            2417.8                                                                            2421.3               CD75       106-122                                                                             IPRLQKIWKNYLSNNKY  256   17   DR8-3-66                                                                            2195.6                                                                            2202.1               c-myc transfor. prot.                                                                    371-385                                                                             KRSFFALRDQIPDL     257   14   DR8-3-68                                                                            1706.0                                                                            1709.6               K-ras trasnfor. prot.                                                                    164-180                                                                             RQYRLKKISKEEKTPGC  258   17   DR8-3-54                                                                            2064.4                                                                            2066.5               Calcitonin 38-53 EPFLYILGKSRVLEAQ   69    16   DR8-3-78                                                                            1863.2                                                                            1848.4               receptor (Hum?)                                                               α-ENOLASE (?)                                                                      23-?  AEVYHDVAASEFF . . .                                                                              259   ?    DR8-3-54                                                                            --  --                   Plasminogen activator                                                                    378-396                                                                             DRPFLFVVRHNPTGTVLFM                                                                              260   19   DR8-3-59                                                                            2246.7                                                                            2247.1               inhibitor-1                                                                              133-148                                                                             NPHFFRLFRSTVKQVD   261   16   DR8-3-70                                                                            2008.4                                                                            2116.4               Apolipoprotein B-100                                                                     1724-1743                                                                           KNIFHFKVNQEGLKLSNDMM                                                                             262   20   DR8-3-62                                                                            2393.8                                                                            2399.4                          1724-1739                                                                           KNIFHFKVNQEGLKLS   263   16   DR8-3-57                                                                            1902.2                                                                            1903.7                          1780-1799                                                                           YKQTVSLDIQPYSLVTTLNS                                                                             264   20   DR8-3-54                                                                            2271.5                                                                            2273.7                          2646-2662                                                                           STPEFTILNTLHIPSFT  265   17   DR8-3-80                                                                            1918.2                                                                            1929.4                          2647-2664                                                                           TPEFTILNTLHIPSFTID 266   18   DR8-3-80                                                                            2059.3                                                                            2073.5                          2647-2662                                                                           TPEFTILNTLHIPSFT   267   16   DR8-3-80                                                                            1831.1                                                                            1841.6                          2885-2900                                                                           SNTKYFHKLNIPQLDF   268   16   DR8-3-68                                                                            1965.2                                                                            1969.9                          2072-2088                                                                           LPFFKFLPKYFEKKRNT  269   17   DR8-3-75                                                                            2203.6                                                                            2207.0                          2072-2086                                                                           LPFFKFLPKYFEKKR    270   15   DR8-3-76                                                                            1988.4                                                                            1992.6                          4022-4036                                                                           WNFYYSPQSSPDKKL    271   15   DR8-3-59                                                                            1860.0                                                                            1863.3               Bovine Transferrin                                                                       261-281                                                                             DVIWELLNHAQEHFGKDKSKE                                                                            272   21   DR8-3-76                                                                            2523.8                                                                            2524.9                          261-275                                                                             DVIWELLINHAQEHFG   273   15   DR8-3-78                                                                            1808.0                                                                            1818.1                          261-273                                                                             DVIWELLNHAQEH      196   13   DR8-3-73                                                                            603.8                                                                             1608.8               von Willebrand factor                                                                    617-636                                                                             IALLLNASQEPQRMSRNFVR                                                                             100   20   DR8-3-59                                                                            2360.8                                                                            2359.7                          617-630                                                                             IALLLNASQEPQRM     189   14   DR8-3-59                                                                            1600.9                                                                            1601.3                                                                        MALD-MS              __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________    HOM2/HLA-DR1 NATURALLY PROCESSED PEPTIDES                                     PROTEIN SOURCE                                                                           POSITION                                                                            SEQUENCE           SEQ ID NO.                                                                          LENGTH                                                                             FRACTION                                                                            MW  MASS                 __________________________________________________________________________                                                             SPEC                 Pseudo HLA-A2                                                                            103-117                                                                             VGSDWRFLRGYHQYA    2     15   H2/DR1-1-64                                                                         1855.0                                                                            1854.4                          104-117                                                                             GSDWRFLRGYHQYA     4     14   H2/DR1-1-63                                                                         1755.3                                                                            1755.2               Invariant Chain                                                                           98-121                                                                             LPKPPKPVSKMRMATPLLMQALPM                                                                         7     24   H2/DR1-1-77                                                                         2676.4                                                                            2675.9               (Ii)        99-122                                                                             PKPPKPVSKMRMATPLLMQALPMG                                                                         8     24   H2/DR1-1-72                                                                         2620.2                                                                            2619.7                           98-120                                                                             LPKPPKPVSKMRMATPLLMQALP                                                                          9     23   H2/DR1-1-73                                                                         2545.2                                                                            2544.5                           99-121                                                                             PKPPKPVSKMRMATPLLMQALPM                                                                          10    23   H2/DR1-1-75                                                                         2563.2                                                                            2562.3                          100-121                                                                             KPPKPVSKMRMATPLLMQALPM                                                                           11    22   H2/DR1-1-75                                                                         2466.1                                                                            2465.8                           99-120                                                                             PKPPKPVSKMRMATPLLMQALP                                                                           12    22   H2/DR1-1-72                                                                         2432.0                                                                            2431.7                          100-120                                                                             KPPKPVSKMRMATPLLMQALP                                                                            13    21   H2/DR1-1-72                                                                         2334.9                                                                            2334.2                                                                        ESI-MS               __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________    SUMMARY OF NATURALLY PROCESSED PEPTIDES BOUND TO HLA-DR EXPRESSED IN          NORMAL HUMAN SPLEEN                                                           PROTEIN SOURCE                                                                           POSITION                                                                            SEQUENCE           SEQ ID NO.                                                                          LENGTH                                                                             MW    MASS                     __________________________________________________________________________                                                         SPEC                     HLA-DR α-chain                                                                     71/133-156                                                                          SETVFLPREDHLFRKFHYLPFLPS                                                                         140   24   2976  2982                                71/136-156                                                                          VFLPREDHLFRKFHYLPFLPS                                                                            141   21   2659  2666                                71/136-155                                                                          VFLPREpHLFRKFHYLPFLP                                                                             142   20   2572  2579                                71/136-151                                                                          VFLPREDHLFRKFHYL   143   16   2118  2126                     Calgranulin B                                                                            33/25-33                                                                            KLGHPDTLN          144   9    994   999                                 42/88-114                                                                           WASHEKMHEGDEGPGHHHKPGLGEGTP                                                                      145   27   2915  2927                                43/88-114                                                                           WASHEKMHEGDEGPGHHHKPGLGEGTP                                                                      146   27   2017  2926                     HLA-B51    42/104-121                                                                          GPDGRLLRGHNQYDGK   188   16   2017  2023                     Kinase C ξ chain (rat)                                                                42/341-446                                                                          TLPPFQPQITDDYGLD   70    16   1104  1705                     HLA-DR4 β chain                                                                     45/129-144                                                                          VRWFRNGQEEKTGVVS   71    16   1892  1894                                                                          MALD-MS                  __________________________________________________________________________

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 274                                                (2) INFORMATION FOR SEQ ID NO: 1:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:                                      ValGlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAlaTyr                              151015                                                                        AspGly                                                                        (2) INFORMATION FOR SEQ ID NO: 2:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:                                      ValGlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAla                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 3:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:                                      ValGlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyr                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 4:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:                                      GlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAla                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 5:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:                                      SerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAla                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 6:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 25                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:                                      LeuProLysProProLysProValSerLysMetArgMetAlaThrPro                              151015                                                                        LeuLeuMetGlnAlaLeuProMetGly                                                   2025                                                                          (2) INFORMATION FOR SEQ ID NO: 7:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7:                                      LeuProLysProProLysProValSerLysMetArgMetAlaThrPro                              151015                                                                        LeuLeuMetGlnAlaLeuProMet                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO: 8:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8:                                      ProLysProProLysProValSerLysMetArgMetAlaThrProLeu                              151015                                                                        LeuMetGlnAlaLeuProMetGly                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO: 9:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9:                                      LeuProLysProProLysProValSerLysMetArgMetAlaThrPro                              151015                                                                        LeuLeuMetGlnAlaLeuPro                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 10:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:                                     ProLysProProLysProValSerLysMetArgMetAlaThrProLeu                              151015                                                                        LeuMetGlnAlaLeuProMet                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 11:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:                                     LysProProLysProValSerLysMetArgMetAlaThrProLeuLeu                              151015                                                                        MetGlnAlaLeuProMet                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 12:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12:                                     ProLysProProLysProValSerLysMetArgMetAlaThrProLeu                              151015                                                                        LeuMetGlnAlaLeuPro                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 13:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13:                                     LysProProLysProValSerLysMetArgMetAlaThrProLeuLeu                              151015                                                                        MetGlnAlaLeuPro                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 14:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14:                                     ProProLysProValSerLysMetArgMetAlaThrProLeuLeuMet                              151015                                                                        GlnAlaLeuPro                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 15:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15:                                     LysMetArgMetAlaThrProLeuLeuMetGlnAlaLeuProMet                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 16:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:                                     LysMetArgMetAlaThrProLeuLeuMetGlnAlaLeuPro                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 17:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:                                     IleProAlaAspLeuArgIleIleSerAlaAsnGlyCysLysValAsp                              151015                                                                        AsnSer                                                                        (2) INFORMATION FOR SEQ ID NO: 18:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18:                                     ArgValGluTyrHisPheLeuSerProTyrValSerProLysGluSer                              151015                                                                        Pro                                                                           (2) INFORMATION FOR SEQ ID NO: 19:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19:                                     TyrLysHisThrLeuAsnGlnIleAspSerValLysValTrpProArg                              151015                                                                        ArgProThr                                                                     (2) INFORMATION FOR SEQ ID NO: 20:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20:                                     TyrLysHisThrLeuAsnGlnIleAspSerValLysValTrpProArg                              151015                                                                        ArgPro                                                                        (2) INFORMATION FOR SEQ ID NO: 21:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21:                                     AspValGlyGluTyrArgAlaValThrGluLeuGlyArgProAspAla                              151015                                                                        GluTyrTrp                                                                     (2) INFORMATION FOR SEQ ID NO: 22:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22:                                     GluProGlyGluProGluPheLysTyrIleGlyAsnMetHisGly                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 23:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23:                                     TyrLysHisThrLeuAsnGlnIleAspSerValLysValTrpProArg                              151015                                                                        Arg                                                                           (2) INFORMATION FOR SEQ ID NO: 24:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24:                                     ProLysTyrValLysGlnAsnThrLeuLysLeuAlaThr                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 25:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25:                                     LeuProLysProProLysProValSerLysMetArgMetAlaThr                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 26:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26:                                     SerAspLeuSerPheSerLysAspTrpSerPheTyrLeu                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 27:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27:                                     LysValPheGlyArgCysGluLeuAlaAlaAlaMetLysArgHisGly                              151015                                                                        LeuAsp                                                                        (2) INFORMATION FOR SEQ ID NO: 28:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28:                                     ArgAsnArgCysLysGlyThrAspValGlnAlaTrpIleArgGlyCys                              151015                                                                        ArgLeu                                                                        (2) INFORMATION FOR SEQ ID NO: 29:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29:                                     HisProProHisIleGluIleGlnMetLeuLysAsnGlyLysLysIle                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 30:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30:                                     AsnGluLeuGlyArgPheLysHisThrAspAlaCysCysArgThrHis                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 31:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31:                                     SerLysProLysValTyrGlnTrpPheAspLeuArgLysTyr                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 32:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32:                                     AlaThrSerThrLysLysLeuHisLysGluProAlaThrLeuIleLys                              151015                                                                        AlaIleAspGly                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 33:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33:                                     ProAlaThrLeuIleLysAlaIleAspGlyAspThrValLysLeuMet                              151015                                                                        TyrLysGlyGln                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 34:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34:                                     AspArgValLysLeuMetTyrLysGlyGlnProMetThrPheArgLeu                              151015                                                                        LeuLeuValAsp                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 35:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35:                                     ValAlaTyrValTyrLysProAsnAsnThrHisGluGlnHisLeuArg                              151015                                                                        LysSerGluAla                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 36:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36:                                     GlnLysGlnGluProIleAspLysGluLeuTyrProLeuThrSerLeu                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 37:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37:                                     GlyAlaArgAlaSerValLeuSerGlyGlyGluLeuAspLysTrpGlu                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 38:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38:                                     ArgThrLeuTyrGlnAsnValGlyThrTyrValSerValGlyThrSer                              151015                                                                        ThrLeuAsnLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 39:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39:                                     LeuLysLysLeuValPheGlyTyrArgLysProLeuAspAsnIle                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 40:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40:                                     LysHisIleGluGlnTyrLeuLysLysIleLysAsnSer                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 41:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41:                                     AspValPheLysGluLeuLysValHisHisAlaAsnGluAsnIlePhe                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 42:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42:                                     GlyAspThrArgProArgPheLeuTrpGlnLeuLysPheGluCysHis                              151015                                                                        PhePheAsnGly                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 43:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43:                                     ThrGluArgValArgLeuLeuGluArgCysIleTyrAsnGlnGluGlu                              151015                                                                        SerValArgPheAspSer                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 44:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 25                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44:                                     AspLeuLeuGluGlnArgArgAlaAlaValAspThrTyrCysArgHis                              151015                                                                        AsnTyrGlyValGlyGluSerPheThr                                                   2025                                                                          (2) INFORMATION FOR SEQ ID NO: 45:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:                                     LysAlaGluArgAlaAspLeuIleAlaTyrLeuLysGlnAlaThrAla                              151015                                                                        Lys                                                                           (2) INFORMATION FOR SEQ ID NO: 46:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46:                                     GlyArgThrGlnAspGluAsnProValValHisPhePheLysAsnIle                              151015                                                                        ValThrProArgThrProProPro                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO: 47:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47:                                     ProLeuLysAlaGluIleAlaGlnArgLeuGluAspVal                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 48:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:                                     ArgGlnIleLeuGlyGlnLeuGlnProSerLeuGlnThrGlySerGlu                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 49:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49:                                     IleGlnValTyrSerArgHisProProGluAsnGlyLysProAsnIle                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 50:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50:                                     IleAsnThrLysCysTyrLysLeuGluHisProValThrGlyCysGly                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 51:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51:                                     TyrLysLeuAsnPheTyrPheAspLeuLeuArgAlaLysLeu                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 52:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52:                                     IleAspThrLeuLysLysAsnGluAsnIleLysGluLeu                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 53:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53:                                     AspValGlyGluTyrArgAlaValThrGluLeuGlyArgProAspAla                              151015                                                                        GluTyrTrpAsn                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 54:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54:                                     GluArgPheAlaValAsnProGlyLeuLeuGluThrSerGluGlyCys                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 55:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55:                                     AspAsnTyrArgGlyTyrSerLeuGlyAsnTrpValCysAlaAlaLys                              151015                                                                        PheGluSerAsnPheThrGln                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 56:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56:                                     GluAlaLeuValArgGlnGlyLeuAlaLysValAlaTyrValTyrLys                              151015                                                                        ProAsnAsnThr                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 57:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57:                                     ProIleValGlnAsnLeuGlnGlyGlnMetValHisGlnAlaIleSer                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 58:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58:                                     SerAlaLeuSerGluGlyAlaThrProGlnAspLeuAsnThrMetLeu                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 59:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59:                                     SerPheTyrIleLeuAlaHisThrGluPheThrProThrGluThrAsp                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 60:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60:                                     LysMetTyrPheAsnLeuIleAsnThrLysCysTyrLysLeuGluHis                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 61:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61:                                     ValGlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAlaTyr                              151015                                                                        AlaAsp                                                                        (2) INFORMATION FOR SEQ ID NO: 62:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62:                                     GlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAlaTyrAsp                              151015                                                                        Gly                                                                           (2) INFORMATION FOR SEQ ID NO: 63:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63:                                     ProProLysProValSerLysMetArgMetAlaThrProLeuLeuMet                              151015                                                                        GlnAlaLeuPro                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 64:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64:                                     LysMetArgMetAlaThrProLeuLeuMetGlnAlaLeuProMetGly                              151015                                                                        AlaLeuPro                                                                     (2) INFORMATION FOR SEQ ID NO: 65:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:                                     GluHisHisIlePheLeuGlyAlaThrAsnTyrIleTyrValLeuAsn                              151015                                                                        GluGluAspLeuGlnLysVal                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 66:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66:                                     GlnGluLeuLysAsnLysTyrTyrGlnValProArgLysGlyIleGln                              151015                                                                        Ala                                                                           (2) INFORMATION FOR SEQ ID NO: 67:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67:                                     IleGlnAsnLeuIleLysGluGluAlaPheLeuGlyIleThrAspGlu                              151015                                                                        LysThrGluGly                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 68:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68:                                     ThrAlaPheGlnTyrIleIleAspAsnLysGlyIleAspSerAspAla                              151015                                                                        Ser                                                                           (2) INFORMATION FOR SEQ ID NO: 69:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69:                                     GluProPheLeuTyrIleLeuGlyLysSerArgValLeuGluAlaGln                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 70:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 70:                                     ThrLeuProProPheGlnProGlnIleThrAspAspTyrGlyLeuAsp                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 71:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71:                                     ValArgTrpPheArgAsnGlyGlnGluGluLysThrGlyValValSer                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 72:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72:                                     ArgValGlnProLysValThrValTyrProSerLysThrGlnProLeu                              151015                                                                        GlnHis                                                                        (2) INFORMATION FOR SEQ ID NO: 73:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73:                                     ArgValGlnProLysValThrValTyrProSerLysThrGlnPro                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 74:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74:                                     AsnPheLeuLysSerAspGlyArgIleLysTyrThrLeuAsnLysAsn                              151015                                                                        SerLeuLys                                                                     (2) INFORMATION FOR SEQ ID NO: 75:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75:                                     IleProAspAsnLeuPheLeuLysSerAspGlyArgIleLysTyrThr                              151015                                                                        LeuAsnLys                                                                     (2) INFORMATION FOR SEQ ID NO: 76:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76:                                     AsnLeuPheLeuLysSerAspGlyArgIleLysTyrThrLeuAsnLys                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 77:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77:                                     AsnLeuPheLeuLysSerAspGlyArgIleLysTyrThrLeuAsn                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 78:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78:                                     TyrAlaAsnIleLeuLeuAspArgArgValProGlnThrAspMetThr                              151015                                                                        Phe                                                                           (2) INFORMATION FOR SEQ ID NO: 79:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79:                                     GlyAspThrArgProArgPheLeuGluTyrSerThrSerGluCysHis                              151015                                                                        PhePhe                                                                        (2) INFORMATION FOR SEQ ID NO: 80:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80:                                     LysHisLysValTyrAlaCysGluValThrHisGlnGlyLeuSerSer                              151015                                                                        ProValThrLysSer                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 81:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81:                                     LysHisLysValTyrAlaCysGluValThrHisGlnGlyLeuSerSer                              151015                                                                        ProValThrLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 82:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82:                                     HisLysValTyrAlaCysGluValThrHisGlnGlyLeuSerSerPro                              151015                                                                        ValThr                                                                        (2) INFORMATION FOR SEQ ID NO: 83:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83:                                     LysHisLysValTyrAlaCysGluValThrHisGlnGlyLeuSerSer                              151015                                                                        Pro                                                                           (2) INFORMATION FOR SEQ ID NO: 84:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84:                                     GluLysHisLysValTyrAlaCysGluValThrHisGlnGlyLeuSer                              151015                                                                        Ser                                                                           (2) INFORMATION FOR SEQ ID NO: 85:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85:                                     LysHisLysValTyrAlaCysGluValThrHisGlnGlyLeuSerSer                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 86:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86:                                     HisLysValTyrAlaCysGluValThrHisGlnGlyLeuSerSerPro                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 87:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87:                                     GluLysHisLysValTyrAlaCysGluValThrHisGlnGlyLeuSer                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 88:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88:                                     LysHisLysValTyrAlaCysGluValThrHisGlnGlyLeuSer                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 89:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89:                                     HisLysValTyrAlaCysGluValThrHisGlnGlyLeuSerSer                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 90:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 90:                                     GluLysHisLysValTyrAlaCysGluValThrHisGlnGly                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 91:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91:                                     AlaProSerProLeuProGluThrThrGluAsnValValCysAlaLeu                              151015                                                                        Gly                                                                           (2) INFORMATION FOR SEQ ID NO: 92:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92:                                     ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerGln                              151015                                                                        ArgMetGluProArg                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 93:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93:                                     ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerGln                              151015                                                                        ArgMetGluPro                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 94:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94:                                     ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerGln                              151015                                                                        ArgMetGlu                                                                     (2) INFORMATION FOR SEQ ID NO: 95:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 95:                                     AspThrGlnPheValArgPheAspSerAspAlaAlaSerGlnArgMet                              151015                                                                        GluProArg                                                                     (2) INFORMATION FOR SEQ ID NO: 96:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96:                                     ThrGlnPheValArgPheAspSerAspAlaAlaSerGlnArgMetGlu                              151015                                                                        ProArgAla                                                                     (2) INFORMATION FOR SEQ ID NO: 97:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 97:                                     ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerGln                              151015                                                                        Arg                                                                           (2) INFORMATION FOR SEQ ID NO: 98:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98:                                     ThrGlnPheValArgPheAspSerAspAlaAlaSerGlnArgMetGlu                              151015                                                                        Pro                                                                           (2) INFORMATION FOR SEQ ID NO: 99:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99:                                     ThrGlnPheValArgPheAspSerAspAlaAlaSerGlnArgMet                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 100:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100:                                    ThrGlnPheValArgPheAspSerAspAlaAlaSer                                          1510                                                                          (2) INFORMATION FOR SEQ ID NO: 101:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerPro                              151015                                                                        ArgGlyGluProArgAlaPro                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 102:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102:                                    ThrGlnPheValArgPheAspSerAspAlaAlaSerProArgGlyGlu                              151015                                                                        ProArgAlaProTrpVal                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 103:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 103:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerPro                              151015                                                                        ArgGlyGluProArg                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 104:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerPro                              151015                                                                        ArgGlyGluPro                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 105:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerPro                              151015                                                                        ArgGlyGlu                                                                     (2) INFORMATION FOR SEQ ID NO: 106:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerPro                              151015                                                                        ArgGly                                                                        (2) INFORMATION FOR SEQ ID NO: 107:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107:                                    ThrGlnPheValArgPheAspSerAspAlaAlaSerProArgGlyGlu                              151015                                                                        ProArg                                                                        (2) INFORMATION FOR SEQ ID NO: 108:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerPro                              151015                                                                        Arg                                                                           (2) INFORMATION FOR SEQ ID NO: 109:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109:                                    AspThrGlnPheValArgPheAspSerAspAlaAlaSerProArgGly                              151015                                                                        Glu                                                                           (2) INFORMATION FOR SEQ ID NO: 110:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110:                                    ThrGlnPheValArgPheAspSerAspAlaAlaSerProArg                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 111:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111:                                    ThrGlnPheValArgPheAspSerAspAlaAlaSer                                          1510                                                                          (2) INFORMATION FOR SEQ ID NO: 112:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112:                                    LeuArgSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGlnArg                              151015                                                                        LysTrpGluAlaAla                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 113:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113:                                    AspLeuArgSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGln                              151015                                                                        Arg                                                                           (2) INFORMATION FOR SEQ ID NO: 114:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114:                                    AspLeuArgSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGln                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 115:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115:                                    AspLeuArgSerTrpThrAlaAlaAspThrAlaAlaGlnIleThr                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 116:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116:                                    AspLeuSerSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGln                              151015                                                                        Arg                                                                           (2) INFORMATION FOR SEQ ID NO: 117:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117:                                    AspLeuSerSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGln                              151015                                                                        ArgLysTrpGlu                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 118:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118:                                    TyrAspHisAsnPheValLysAlaIleAsnAlaAspGlnLysSerTrp                              151015                                                                        Thr                                                                           (2) INFORMATION FOR SEQ ID NO: 119:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 119:                                    TyrAspHisAsnPheValLysAlaIleAsnAlaAspIleLysSerTrp                              151015                                                                        Thr                                                                           (2) INFORMATION FOR SEQ ID NO: 120:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 120:                                    TyrAspHisAsnPheValLysAlaIleAsnAlaAspGlnLysSerTrp                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 121:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121:                                    TyrAspHisAsnPheValLysAlaIleAsnAlaIleGlnLysSerTrp                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 122:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 122:                                    GlyAspThrArgProArgPheLeuGluGlnValLysHisGlu                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 123:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 123:                                    GlyValTyrPheTyrLeuGlnTrpGlyArgSerThrLeuValSerVal                              151015                                                                        Ser                                                                           (2) INFORMATION FOR SEQ ID NO: 124:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 124:                                    ArgProAlaGlyAspGlyThrPheGlnLysTrpAlaSerValValVal                              151015                                                                        ProSerGlyGln                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 125:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 125:                                    ArgProAlaGlyAspGlyThrPheGlnLysTrpAlaSerValValVal                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 126:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 126:                                    GlyAspGlyThrPheGlnLysTrpAlaSerValValValProSerGly                              151015                                                                        GlnGluGlnArgTyrThr                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 127:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 127:                                    GlyAspGlyThrPheGlnLysTrpAlaSerValValValProSerGly                              151015                                                                        GlnGlu                                                                        (2) INFORMATION FOR SEQ ID NO: 128:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 128:                                    GlyThrPheGlnLysTrpAlaSerValValValProSerGly                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 129:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 129:                                    GlyThrPheGlnLysTrpAlaSerValValValProSerGlyGln                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 130:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 130:                                    GlyThrPheGlnLysTrpAlaSerValValValProSerGlyGlnGlu                              151015                                                                        GlnArgTyrThrCysHisVal                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 131:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 131:                                    GlyAlaLeuAlaAsnIleAlaValAspLysAlaAsnLeuGluIleMet                              151015                                                                        ThrLysArgSerAsn                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 132:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 132:                                    ThrProSerTyrValAlaPheThrAspThrGluArgLeuIleGlyAsp                              151015                                                                        Ala                                                                           (2) INFORMATION FOR SEQ ID NO: 133:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133:                                    ThrProSerTyrValAlaPheThrAspThrGluArgLeuIleGly                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 134:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 134:                                    ArgSerGluGluPheLeuIleAlaGlyLysLeuGlnAspGlyLeuLeu                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 135:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 135:                                    SerGluGluPheLeuIleAlaGlyLysLeuGlnAspGlyLeuLeu                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 136:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 136:                                    AspValIleTrpGluLeuLeuAsnHisAlaGlnGluHisPheGly                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 137:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 137:                                    GluProPheLeuTyrIleLeuGlyLysSerArgValLeuGluAlaGln                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 138:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 138:                                    ThrAlaPheGlnTyrIleIleAspAsnLysGlyIleAspSerAsp                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 139:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 139:                                    ThrAlaPheGlnTyrIleIleAspAsnLysGlyIleAspSer                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 140:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 140:                                    SerGluThrValPheLeuProArgGluAspHisLeuPheArgLysPhe                              151015                                                                        HisTyrLeuProPheLeuProSer                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO: 141:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 141:                                    ValPheLeuProArgGluAspHisLeuPheArgLysPheHisTyrLeu                              151015                                                                        ProPheLeuProSer                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 142:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 142:                                    ValPheLeuProArgGluAspHisLeuPheArgLysPheHisTyrLeu                              151015                                                                        ProPheLeuPro                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 143:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 143:                                    ValPheLeuProArgGluAspHisLeuPheArgLysPheHisTyrLeu                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 144:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 144:                                    LysLeuGlyHisProAspThrLeuAsnGlnGlyGluPheLysGluLeu                              151015                                                                        ValArgLysAspLeuGlnAsnPheLeuLys                                                2025                                                                          (2) INFORMATION FOR SEQ ID NO: 145:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 145:                                    LysLeuGlyHisProAspThrLeuAsnGlnGlyGluPheLysGluLeu                              151015                                                                        ValArgLysAspLeuGlnAsnPhe                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO: 146:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 146:                                    LysLeuGlyHisProAspThrLeuAsnGlnGlyGluPheLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 147:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 123                                                               (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 147:                                    ATGGCCATAAGTGGAGTCCCTGTGCTAGGATTTTTCATCATAGCTGTG48                            MetAlaIleSerGlyValProValLeuGlyPhePheIleIleAlaVal                              151015                                                                        CTGATGAGCGCTCAGGAATCATGGGCTAAGATGCGCATGGCCACCCCG96                            LeuMetSerAlaGlnGluSerTrpAlaLysMetArgMetAlaThrPro                              202530                                                                        CTGCTGATGCAGGCGCTGCCCATGTAA123                                                LeuLeuMetGlnAlaLeuProMet                                                      3540                                                                          (2) INFORMATION FOR SEQ ID NO: 148:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 150                                                               (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 148:                                    ATGGCCATAAGTGGAGTCCCTGTGCTAGGATTTTTCATCATAGCTGTG48                            MetAlaIleSerGlyValProValLeuGlyPhePheIleIleAlaVal                              151015                                                                        CTGATGAGCGCTCAGGAATCATGGGCTCTTCCCAAGCCTCCCAAGCCT96                            LeuMetSerAlaGlnGluSerTrpAlaLeuProLysProProLysPro                              202530                                                                        GTGAGCAAGATGCGCATGGCCACCCCGCTGCTGATGCAGGCGCTGCCC144                           ValSerLysMetArgMetAlaThrProLeuLeuMetGlnAlaLeuPro                              354045                                                                        ATGTAA150                                                                     Met                                                                           (2) INFORMATION FOR SEQ ID NO: 149:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 149:                                    ThrGlnPheValArgPheAspSerAspAla                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO: 150:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 150:                                    AspTrpArgPheLeuArgGlyTyrHisGln                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO: 151:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 151:                                    ArgMetAlaThrProLeuLeuMetGlnAla                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO: 152:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4                                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 152:                                    LysAspGluLeu                                                                  (2) INFORMATION FOR SEQ ID NO: 153:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5                                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 153:                                    LysPheGluArgGln                                                               15                                                                            (2) INFORMATION FOR SEQ ID NO: 154:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5                                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 154:                                    GlnArgGluPheLys                                                               15                                                                            (2) INFORMATION FOR SEQ ID NO: 155:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 25                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 155:                                    MetAlaIleSerGlyValProValLeuGlyPhePheIleIleAlaVal                              151015                                                                        LeuMetSerAlaGlnGluSerTrpAla                                                   2025                                                                          (2) INFORMATION FOR SEQ ID NO: 156:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 156:                                    MetArgMetAlaThrProLeuLeuMetGlnAlaLeuProMet                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 157:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 157:                                    MetProArgSerArgAlaLeuIleLeuGlyValLeuAlaLeuThrThr                              151015                                                                        MetLeuSerLeuCysGlyGly                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 158:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 158:                                    AsnIleValIleLysArgSerAsnSerThrAlaAlaThrAsnGluVal                              151015                                                                        ProGluValThrValPheSer                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 159:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 159:                                    AsnIleValIleLysArgSerAsnSerThrAlaAlaThrAsnGluVal                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 160:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 160:                                    SerAspValGlyValTyrArgAlaValThrProGlnGlyArgProAsp                              151015                                                                        AlaGlu                                                                        (2) INFORMATION FOR SEQ ID NO: 161:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 161:                                    AspValGlyValTyrArgAlaValThrProGlnGlyArgProAspAla                              151015                                                                        Glu                                                                           (2) INFORMATION FOR SEQ ID NO: 162:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 162:                                    AspValGlyValTyrArgAlaValThrProGlnGlyArgProAsp                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 163:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 163:                                    AlaProSerProLeuProGluThrThrGluAsnValVal                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 164:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 164:                                    AlaProSerProLeuProGluThrThrGluAsnValValCysAlaLeu                              151015                                                                        Gly                                                                           (2) INFORMATION FOR SEQ ID NO: 165:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 165:                                    PheProLysSerLeuHisThrTyrAlaAsnIleLeuLeuAspArgArg                              151015                                                                        ValProGlnThrAsp                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 166:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 166:                                    PheProLysSerLeuHisThrTyrAlaAsnIleLeuLeuAspArgArg                              151015                                                                        ValProGln                                                                     (2) INFORMATION FOR SEQ ID NO: 167:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 167:                                    AspGlyIleLeuTyrTyrTyrGlnSerGlyGlyArgLeuArgArgPro                              151015                                                                        ValAsn                                                                        (2) INFORMATION FOR SEQ ID NO: 168:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 168:                                    AspGlyIleLeuTyrTyrTyrGlnSerGlyGlyArgLeuArgArgPro                              151015                                                                        Val                                                                           (2) INFORMATION FOR SEQ ID NO: 169:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 169:                                    LeuSerProIleHisIleAlaLeuAsnPheSerLeuAspProGlnAla                              151015                                                                        ProValAspSerHisGlyLeuArgProAlaLeuHisTyrGln                                    202530                                                                        (2) INFORMATION FOR SEQ ID NO: 170:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 170:                                    LeuTrpAspTyrGlyMetSerSerSerProHisValLeuArgAsnArg                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 171:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 171:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerGln                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 172:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 172:                                    ProProGluValThrValLeuThrAsnSerProValGluLeuArgGlu                              151015                                                                        ProAsnVal                                                                     (2) INFORMATION FOR SEQ ID NO: 173:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 173:                                    ProProGluValThrValLeuThrAsnSerProValGluLeuArgGlu                              151015                                                                        ProAsn                                                                        (2) INFORMATION FOR SEQ ID NO: 174:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 174:                                    ValPheLeuLeuLeuLeuAlaAspLysValProGluThrSerLeuSer                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 175:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 175:                                    ThrPheAspGluIleAlaSerGlyPheArgGlnGlyGlyAlaSerGln                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 176:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 176:                                    TyrGlyTyrThrSerTyrAspThrPheSerTrpAlaPheLeu                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 177:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 177:                                    AlaThrLysTyrGlyAsnMetThrGluAspHisValMetHisLeuLeu                              151015                                                                        GlnAsnAla                                                                     (2) INFORMATION FOR SEQ ID NO: 178:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 178:                                    GlyGlnValLysLysAsnAsnHisGlnGluAspLysIleGlu                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 179:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 179:                                    LeuAsnLysIleLeuLeuAspGluGlnAlaGlnTrpLys                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 180:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 180:                                    GlyProProLysLeuAspIleArgLysGluGluLysGlnIleMetIle                              151015                                                                        AspIlePheHis                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 181:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 181:                                    GlyProProLysLeuAspIleArgLysGluGluLysGlnIleMetIle                              151015                                                                        AspIlePheHisPro                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 182:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 182:                                    SerProLeuGlnAlaLeuAspPhePheGlyAsnGlyProProValAsn                              151015                                                                        TyrLysThrGlyAsnLeu                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 183:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 183:                                    SerProLeuGlnAlaLeuAspPhePheGlyAsnGlyProProValAsn                              151015                                                                        TyrLysThrGly                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 184:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 184:                                    GlyLysPheAlaIleArgProAspLysLysSerAsnProIleIleArg                              151015                                                                        ThrVal                                                                        (2) INFORMATION FOR SEQ ID NO: 185:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 185:                                    ThrGlyHisGlyAlaArgThrSerThrGluProThrThrAspTyr                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 186:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 186:                                    LysGluLeuLysArgGlnTyrGluLysLysLeuArgGln                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 187:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 187:                                    AspAspThrGlnPheValArgPheAspSerAspAla                                          1510                                                                          (2) INFORMATION FOR SEQ ID NO: 188:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 188:                                    GlyProAspGlyArgLeuLeuArgGlyHisAsnGlnTyrAspGlyLys                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 189:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 189:                                    IleAlaLeuLeuLeuMetAlaSerGlnGluProGlnArgMet                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 190:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 190:                                    IleAlaLeuLeuLeuMetAlaSerGlnGluProGlnArgMetSerArg                              151015                                                                        AsnPheValArg                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 191:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 191:                                    IleProAspAsnLeuPheLeuLysSerAspGlyArgIleLysTyrThr                              151015                                                                        LeuAsnLysAsn                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 192:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 192:                                    IleProAspAsnLeuPheLeuLysSerAspGlyArgIleLysTyrThr                              151015                                                                        LeuAsn                                                                        (2) INFORMATION FOR SEQ ID NO: 193:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 193:                                    IleProAspAsnLeuPheLeuLysSerAspGlyArgIleLysTyrThr                              151015                                                                        Leu                                                                           (2) INFORMATION FOR SEQ ID NO: 194:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 194:                                    ValThrThrLeuAsnSerAspLeuLysTyrAsnAlaLeuAspLeuThr                              151015                                                                        Asn                                                                           (2) INFORMATION FOR SEQ ID NO: 195:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 195:                                    ValAspAspThrGlnPheValArgPheAspSerAspAlaAlaSerGln                              151015                                                                        ArgMetGluProArgAlaPro                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 196:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 196:                                    AspValIleTrpGluLeuLeuAsnHisAlaGlnGluHis                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 197:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 197:                                    AspLeuArgSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGln                              151015                                                                        ArgLysTrp                                                                     (2) INFORMATION FOR SEQ ID NO: 198:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 198:                                    LeuArgSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGlnArg                              151015                                                                        LysTrp                                                                        (2) INFORMATION FOR SEQ ID NO: 199:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 199:                                    AspLeuSerSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGln                              151015                                                                        ArgLysTrpGluAlaAla                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 200:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 200:                                    AspLeuSerSerTrpThrAlaAlaAspThrAlaAlaGlnIleThrGln                              151015                                                                        ArgLys                                                                        (2) INFORMATION FOR SEQ ID NO: 201:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 201:                                    GlySerLeuPheValTyrAsnIleThrThrAsnLysTyrLysAlaPhe                              151015                                                                        LeuAspLysGln                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 202:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 202:                                    GlySerLeuPheValTyrAsnIleThrThrAsnLysTyrLysAlaPhe                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 203:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 203:                                    AlaAlaProTyrGluLysGluValProLeuSerAlaLeuThrAsnIle                              151015                                                                        LeuSerAlaGlnLeu                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 204:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 204:                                    AlaAlaProTyrGluLysGluValProLeuSerAlaLeuThrAsnIle                              151015                                                                        LeuSer                                                                        (2) INFORMATION FOR SEQ ID NO: 205:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 205:                                    AlaGluAlaLeuGluArgMetPheLeuSerPheProThrThrLysThr                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 206:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 206:                                    SerProGluAspPheValTyrGlnPheLysGlyMetCysTyrPhe                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 207:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 207:                                    SerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAlaTyrAspGly                              151015                                                                        LysAspTyrIle                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 208:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 208:                                    GlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAla                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 209:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 209:                                    GlySerAspTrpArgPheLeuArgGlyTyrHisGlnTyr                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 210:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 210:                                    SerAspTrpArgPheLeuArgGlyTyrHisGlnTyrAla                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 211:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 211:                                    ArgGluThrGlnIleSerLysThrAsnThrGlnThrTyrArgGluAsn                              151015                                                                        Leu                                                                           (2) INFORMATION FOR SEQ ID NO: 212:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 212:                                    ArgGluThrGlnIleSerLysThrAsnThrGlnThrTyrArgGluAsn                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 213:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 213:                                    ArgGluThrGlnIleSerLysThrAsnThrGlnThrTyrArgGlu                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 214:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 214:                                    ArgSerAsnTyrThrProIleThrAsnProProGluValThrValLeu                              151015                                                                        ThrAsnSerProValGluLeuArgGluPro                                                2025                                                                          (2) INFORMATION FOR SEQ ID NO: 215:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 215:                                    AlaProSerProLeuProGluThrThrGluAsnValValCysAlaLeu                              151015                                                                        GlyLeuThrVal                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 216:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 216:                                    SerLeuGlnSerProIleThrValGluTrpArgAlaGlnSerGluSer                              151015                                                                        AlaGlnSerLysMetLeuSerGlyIleGlyGlyPheValLeu                                    202530                                                                        (2) INFORMATION FOR SEQ ID NO: 217:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 217:                                    ValThrGlnTyrLeuAsnAlaThrGlyAsnArgTrpCysSerTrpSer                              151015                                                                        LeuSerGlnAlaArg                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 218:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 218:                                    ValThrGlnTyrLeuAsnAlaThrGlyAsnArgTrpCysSerTrpSer                              151015                                                                        Leu                                                                           (2) INFORMATION FOR SEQ ID NO: 219:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 219:                                    ThrSerIleLeuCysTyrArgLysArgGluTrpIleLys                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 220:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 220:                                    LysHisLysValTyrAlaCysGluValThrHisGlnGlyLeu                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 221:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 221:                                    LysHisLysValTyrAlaCysGluValThrHisGlnGly                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 222:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 25                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 222:                                    GlyAspMetTyrProLysThrTrpSerGlyMetLeuValGlyAlaLeu                              151015                                                                        CysAlaLeuAlaGlyValLeuThrIle                                                   2025                                                                          (2) INFORMATION FOR SEQ ID NO: 223:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 223:                                    AlaProValLeuIleSerGlnLysLeuSerProIleTyrAsnLeuVal                              151015                                                                        ProValLys                                                                     (2) INFORMATION FOR SEQ ID NO: 224:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 224:                                    ProAlaPheArgPheThrArgGluAlaAlaGlnAspCysGluVal                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 225:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 225:                                    ValProGlyLeuTyrSerProCysArgAlaPhePheAsnLysGluGlu                              151015                                                                        LeuLeu                                                                        (2) INFORMATION FOR SEQ ID NO: 226:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 226:                                    ValProGlyLeuTyrSerProCysArgAlaPhePheAsnLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 227:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 227:                                    LysValAspLeuThrPheSerLysGlnHisAlaLeuLeuCysSerAsp                              151015                                                                        TyrGlnAlaAspTyrGluSer                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 228:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 228:                                    LysValAspLeuThrPheSerLysGlnHisAlaLeuLeuCysSer                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 229:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 229:                                    PheSerHisAspTyrArgGlySerThrSerHisArgLeu                                       1210                                                                          (2) INFORMATION FOR SEQ ID NO: 230:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 230:                                    LeuProLysTyrPheGluLysLysArgAsnThrIleIle                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 231:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 231:                                    SerGluThrValPheLeuProArgGluAspHisLeuPheArgLysPhe                              151015                                                                        HisTyrLeuProPheLeuPro                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO: 232:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 232:                                    AlaProSerProLeuProGluGluThrThrGluAsnValValCysAla                              151015                                                                        LeuGly                                                                        (2) INFORMATION FOR SEQ ID NO: 233:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 233:                                    GlyAspThrArgProArgPheLeuGluTyrSerThrGlyGluCysTyr                              151015                                                                        PhePheAsnGlyThrGluArgVal                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO: 234:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 234:                                    ArgHisAsnTyrGluLeuAspGluAlaValThrLeuGln                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 235:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 235:                                    AspProGlnSerGlyAlaLeuTyrIleSerLysValGlnLysGluAsp                              151015                                                                        AsnSerThrTyrIle                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 236:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 236:                                    GlyAlaLeuTyrIleSerLysValGlnLysGluAspAsnSerThrTyr                              151015                                                                        Ile                                                                           (2) INFORMATION FOR SEQ ID NO: 237:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 237:                                    AspProValProLysProValIleLysIleGluLysIleGluAspMet                              151015                                                                        AspAsp                                                                        (2) INFORMATION FOR SEQ ID NO: 238:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 238:                                    AspProValProLysProValIleLysIleGluLysIleGluAsp                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 239:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 239:                                    PheThrPheThrIleSerArgLeuGluProGluAspPheAlaValTyr                              151015                                                                        TyrCys                                                                        (2) INFORMATION FOR SEQ ID NO: 240:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 240:                                    PheThrPheThrIleSerArgLeuGluProGluAspPheAlaVal                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 241:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 241:                                    AspProValGluMetArgArgLeuAsnTyrGlnThrProGly                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 242:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 242:                                    TyrGlnLeuLeuArgSerMetIleGlyTyrIleGluGluLeuAlaPro                              151015                                                                        IleVal                                                                        (2) INFORMATION FOR SEQ ID NO: 243:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 243:                                    GlyAsnHisLeuTyrLysTrpLysGlnIleProAspCysGluAsnVal                              151015                                                                        Lys                                                                           (2) INFORMATION FOR SEQ ID NO: 244:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 244:                                    LeuProPhePheLeuPheArgGlnAlaTyrHisProAsnAsnSerSer                              151015                                                                        ProValCysTyr                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 245:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 245:                                    GlnAlaLysPhePheAlaCysIleLysArgSerAspGlySerCysAla                              151015                                                                        TrpTyrArgGlyAlaAlaProProLysGlnGluPhe                                          2025                                                                          (2) INFORMATION FOR SEQ ID NO: 246:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 246:                                    GlnAlaLysPhePheAlaCysIleLysArgSerAspGlySerCysAla                              151015                                                                        TrpTyrArg                                                                     (2) INFORMATION FOR SEQ ID NO: 247:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 247:                                    SerGluGluPheLeuIleAlaGlyLysLeuGlnAspGlyLeuLeu                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 248:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 248:                                    AsnArgSerGluGluPheLeuIleAlaGlyLysLeu                                          1510                                                                          (2) INFORMATION FOR SEQ ID NO: 249:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 249:                                    GlnAsnPheThrValIlePheAspThrGlySerSerAsnLeuTrpVal                              151015                                                                        ProSerValTyrCysThrSerPro                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO: 250:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 250:                                    AspGluTyrTyrArgArgLeuLeuArgValLeuArgAlaArgGluGln                              151015                                                                        IleVal                                                                        (2) INFORMATION FOR SEQ ID NO: 251:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 251:                                    GluAlaIleTyrAspIleCysArgArgAsnLeuAspIleGluArgPro                              151015                                                                        Thr                                                                           (2) INFORMATION FOR SEQ ID NO: 252:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 252:                                    GluAlaIleTyrAspIleCysArgArgAsnLeuAspIle                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 253:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 253:                                    HisGluLeuGluLysIleLysLysGlnValGluGlnGluLysCysGlu                              151015                                                                        IleGlnAlaAlaLeu                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 254:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 254:                                    ArgProSerMetLeuGlnHisLeuLeuArg                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO: 255:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 255:                                    AspAspPheMetGlyGlnLeuLeuAsnGlyArgValLeuPheProVal                              151015                                                                        AsnLeuGlnLeuGlyAla                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 256:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 256:                                    IleProArgLeuGlnLysIleTrpLysAsnTyrLeuSerMetAsnLys                              151015                                                                        Tyr                                                                           (2) INFORMATION FOR SEQ ID NO: 257:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 257:                                    LysArgSerPhePheAlaLeuArgAspGlnIleProAspLeu                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO: 258:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 258:                                    ArgGlnTyrArgLeuLysLysIleSerLysGluGluLysThrProGly                              151015                                                                        Cys                                                                           (2) INFORMATION FOR SEQ ID NO: 259:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 259:                                    AlaGluValTyrHisAspValAlaAlaSerGluPhePhe                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO: 260:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 260:                                    AspArgProPheLeuPheValValArgHisAsnProThrGlyThrVal                              151015                                                                        LeuPheMet                                                                     (2) INFORMATION FOR SEQ ID NO: 261:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 261:                                    MetProHisPhePheArgLeuPheArgSerThrValLysGlnValAsp                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 262:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 262:                                    LysAsnIlePheHisPheLysValAsnGlnGluGlyLeuLysLeuSer                              151015                                                                        AsnAspMetMet                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 263:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 263:                                    LysAsnIlePheHisPheLysValAsnGlnGluGlyLeuLysLeuSer                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 264:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 264:                                    TyrLysGlnThrValSerLeuAspIleGlnProTyrSerLeuValThr                              151015                                                                        ThrLeuAsnSer                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO: 265:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 265:                                    SerThrProGluPheThrIleLeuAsnThrLeuHisIleProSerPhe                              151015                                                                        Thr                                                                           (2) INFORMATION FOR SEQ ID NO: 266:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 266:                                    ThrProGluPheThrIleLeuAsnThrLeuHisIleProSerPheThr                              151015                                                                        IleAsp                                                                        (2) INFORMATION FOR SEQ ID NO: 267:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 267:                                    ThrProGluPheThrIleLeuAsnThrLeuHisIleProSerPheThr                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 268:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 268:                                    SerAsnThrLysTyrPheHisLysLeuAsnIleProGlnLeuAspPhe                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 269:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 269:                                    LeuProPhePheLysPheLeuProLysTyrPheGluLysLysArgAsn                              151015                                                                        Thr                                                                           (2) INFORMATION FOR SEQ ID NO: 270:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 270:                                    LeuProPhePheLysPheLeuProLysTyrPheGluLysLysArg                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 271:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 271:                                    TrpAsnPheTyrTyrSerProGlnSerSerProAspLysLysLeu                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 272:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 272:                                    AspValIleTrpGluLeuLeuAsnHisAlaGlnGluHisPheGlyLys                              151015                                                                        AspLysSerLysGlu                                                               20                                                                            (2) INFORMATION FOR SEQ ID NO: 273:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 273:                                    AspValIleTrpGluLeuLeuIleAsnHisAlaGlnGluHisPheGly                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 274:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23                                                                (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 274:                                    MetProArgSerArgAlaLeuIleLeuGlyValLeuAlaLeuThrThr                              151015                                                                        MetLeuSerLeuCysGlyGly                                                         20                                                                            __________________________________________________________________________

What is claimed is:
 1. A method of decreasing major histocompatibilitycomplex (MHC) class II antigen presentation in a mammal, which methodcomprises introducing into an antigen presenting cell (APC) of saidmammal an expression vector comprising a nucleic acid molecule codingfor the expression of a self peptide having the amino acid sequence of anaturally processed segment of a protein of said mammal, said segmentbeing of 10 to 30 residues in length, wherein said self peptide isnon-immunogenic in said mammal and binds to an MHC class II molecule ofsaid mammal, thereby decreasing MHC clasp II antigen presentation insaid mammal.
 2. The method of claim 1, wherein said expression vectoradditionally comprises expression control elements.
 3. The method ofclaim 1, wherein said expression vector comprises plasmid or viralgenomic sequence.
 4. The method of claim 1, wherein said expressionvector comprises the genome of a non-replicative, non-virulent vacciniavirus, adenovirus, Epstein-Barr virus, or retrovirus.
 5. The method ofclaim 1, wherein said expression vector is administered to said APC in aliposome or ISCOM.
 6. The method of claim 1, wherein said segment bindsto at least two distinct human MHC class II molecule allotypes.
 7. Themethod of claim 1, wherein said protein is HLA-A2, HLA-A29, HLA-A30,HLA-B44, HLA-B51, HLA-Bw62, HLA-C, HLA-DP β-chain, HLA-DQ α-chain,HLA-DQ β-chain, HLA-DQ3.2 β-chain, HLA-DR α-chain, HLA-DR β-chain,HLA-DR4 β-chain, invariant chain (Ii), Ig kappa chain, Ig kappa chain Cregion, Ig heavy chain, Na⁺ /K⁺ ATPase, potassium channel protein,sodium channel protein, calcium release channel protein, complement C9,glucose-transport protein, CD35, CD45, CD75, vinculin, calgranulin B,kinase C ζ-chain, integrin β-4 gp150, hemoglobin, tubulin α-1 chain,myosin β-heavy chain, α-enolase, transferrin, transferrin receptor,fibronectin receptor α-chain, acetylcholine receptor, interleukin-8receptor, interferon α-receptor, interferon γ-receptor, calcitoninreceptor, LAM (lymphocyte activation marker) Blast-1, LAR (leukocyteantigen-related) protein, LIF (leukemia inhibitory factor) receptor, 4F2cell-surface antigen (a cell-surface antigen involved in normal andneoplastic growth) heavy chain, cystatin SN, VLA-4 (a cell surfaceheterodimer in the integrin superfamily of adhesion receptors), PAI-1(plasminogen activator inhibitor-1), IP-30 (interferon-γ inducedprotein), ICAM-2, carboxypeptidase E, thromboxane-A synthase,NADH-cytochrome-b5 reductase, c-myc transforming protein, K-rastransforming protein, MET kinase-related transforming protein,interferon-induced guanylate-binding protein, mannose-binding protein,apolipoprotein B-100, cathepsin C, cathepsin E, cathepsin S, FactorVIII, von Willebrand factor, metalloproteinase inhibitor 1 precursor,metalloproteinase inhibitor 2, plasminogen activator inhibitor-1, orheat shock cognate 71 kD protein.
 8. The method of claim 1, wherein saidprotein is a human MHC class I or MHC class II molecule.
 9. The methodof claim 1, wherein said segment comprises residues 29-40 (SEQ ID NO:187) or residues 106-115 (SEQ ID NO: 150) of HLA-A2 heavy chain.
 10. Themethod of claim 1, wherein said segment comprises residues 108-117 of Ii(SEQ ID NO: 151).
 11. The method of claim 1, wherein said expressionvector is introduced into said APC ex vivo, and subsequently said APC isreintroduced into said mammal.
 12. The method of claim 1, wherein saidexpression vector is introduced into said APC in vivo.
 13. The method ofclaim 8, wherein said segment comprises residues 31-42, 104-116,105-117, 129-145, 129-146, or 130-147 of a human MHC class I heavychain.
 14. The method of claim 8, wherein said segment comprisesresidues 43-57 of a human MHC class II β chain.
 15. The method of claim1, wherein said segment comprises human Ig kappa chain residues 188-200(SEQ ID NO: 221).
 16. The method of claim 1, wherein said mammal is ahuman.
 17. A method of decreasing MHC class II antigen presentation in amammal, which method comprises introducing into an APC of said mammal anexpression vector comprising a nucleic acid molecule encoding apolypeptide consisting of at least one trafficking sequence linked to aself peptide having the amino acid sequence of a segment of a protein ofsaid mammal, said segment being of 10 to 30 residues in length, whereinsaid self peptide is non-immunogenic in said mammal and binds to a MHCclass II molecule of said mammal, thereby decreasing MHC class IIantigen presentation in said mammal.
 18. The method of claim 17, whereinsaid molecule additionally encodes a second polypeptide consisting of asecond self peptide and a second trafficking sequence.
 19. The method ofclaim 17, wherein said segment comprises residues 31-42, 104-116,105-117, 129-145, 129-146, or 130-147 of a human MHC class I heavychain, having the sequence of SEQ ID NO: 100, 209, 5, 113, 200 or 198,respectively.
 20. The method of claim 17, wherein said segment comprisesresidues 43-57 of a human MHC class II β chain (SEQ ID NO: 162).
 21. Themethod of claim 17, wherein said segment comprises human Ig kappa chainresidues 188-200 (SEQ ID NO: 221).
 22. The method of claim 17, whereinsaid mammal is a human.
 23. The method of claim 17, wherein saidexpression vector additionally comprises expression control elements.24. The method of claim 17, wherein said expression vector comprisesplasmid or viral genomic sequence.
 25. The method of claim 17, whereinsaid expression vector comprises the genome of a non-replicative,non-virulent vaccinia virus, adenovirus, Epstein-Barr virus, orretrovirus.
 26. The method of claim 17, wherein said expression vectoris administered to said APC in a liposome or ISCOM.
 27. The method ofclaim 17, wherein said segment binds to at least two distinct human MHCclass II molecule allotypes.
 28. The method of claim 17, wherein saidprotein is HLA-A2, HLA-A29, HLA-A30, HLA-B44, HLA-B51, HLA-Bw62, HLA-C,HLA-DP β-chain, HLA-DQ α-chain, HLA-DQ β-chain, HLA-DQ3.2 β-chain,HLA-DR α-chain, HLA-DR β-chain, HLA-DR4 β-chain, invariant chain (Ii),Ig kappa chain, Ig kappa chain C region, Ig heavy chain, Na⁺ /K⁺ ATPase,potassium channel protein, sodium channel protein, calcium releasechannel protein, complement C9, glucose-transport protein, CD35, CD45,CD75, vinculin, calgranulin B, kinase C ζ-chain, integrin β-4 gp150,hemoglobin, tubulin α-1 chain, myosin β-heavy chain, α-enolase,transferrin, transferrin receptor, fibronectin receptor α-chain,acetylcholine receptor, interleukin-8 receptor, interferon α-receptor,interferon γ-receptor, calcitonin receptor, LAM (lymphocyte activationmarker) Blast-1, LAR (leukocyte antigen-related) protein, LIF (leukemiainhibitory factor) receptor, 4F2 cell-surface antigen (a cell-surfaceantigen involved in normal and neoplastic growth) heavy chain, cystatinSN, VLA-4 (a cell surface heterodimer in the integrin superfamily ofadhesion receptors), PAI-1 (plasminogen activator inhibitor-1), IP-30(interferon-γ induced protein), ICAM-2, carboxypeptidase E,thromboxane-A synthase, NADH-cytochrome-b5 reductase, c-myc transformingprotein, K-ras transforming protein, MET kinase-related transformingprotein, interferon-induced guanylate-binding protein, mannose-bindingprotein, apolipoprotein B-100, cathepsin C, cathepsin E, cathepsin S,Factor VIII, von Willebrand factor, metalloproteinase inhibitor 1precursor, metalloproteinase inhibitor 2, plasminogen activatorinhibitor-1, or heat shock cognate 71 kD protein.
 29. The method ofclaim 17, wherein said protein is a human MHC class I or MHC class IImolecule.
 30. The method of claim 17, wherein said segment comprisesresidues 29-40 (SEQ ID NO: 187) or residues 106-115 (SEQ ID NO: 150) ofHLA-A2 heavy chain.
 31. The method of claim 17, wherein said segmentcomprises residues 108-117 of Ii (SEQ ID NO: 151).
 32. The method ofclaim 17, wherein said expression vector is introduced into said APC exvivo, and subsequently said APC is reintroduced into said mammal. 33.The method of claim 17, wherein said expression vector is introducedinto said APC in vivo.
 34. A method of decreasing MHC class IIpresentation in a human patient, which method comprises introducing intoan APC of said patient an expression vector comprising a nucleic acidmolecule encoding a polypeptide comprising residues 108 to 117 of Ii,said polypeptide comprising no more than 30 residues of Ii, wherein saidpolypeptide is expressed in said APC and presented by an MHC class IImolecule on said APC, thereby decreasing MHC class II antigenpresentation in said patient.
 35. The method of claim 34, wherein saidpolypeptide additionally comprises a trafficking sequence.
 36. Themethod of claim 34, wherein said expression vector is introduced intosaid APC in vitro.
 37. The method of claim 34, wherein said expressionvector is introduced into said APC in vivo.
 38. The method of claim 34,wherein said expression vector additionally comprises expression controlelements.
 39. The method of claim 34, wherein said expression vector isadministered to said APC in a liposome or ISCOM.